Src homology 2 (SH2) domain found in the Cbl-b TKB domain; SH2 found in the Cbl-b TKB domain. The Cbl (for Casitas B-lineage lymphoma) family of E3 ubiquitin ligases contains three members Cbl, Cbl-b and Cbl-c. The founding member Cbl was discovered first as the oncogenic protein v-Cbl, a Gag-fusion transforming protein of Cas NS-1 retrovirus, which causes pre- and pro-B lymphomas in mice. The N-terminus of the Cbl proteins is composed of a tyrosine kinase-binding (TKB) domain, also called phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. In addition, Cbl and Cbl-b contain a leucine zipper motif and a proline-rich domain in the C-terminus. The TKB domain consists of a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. Cbl-b plays a role in early hematopoietic development and is a negative regulator of T-cell receptor, B-cell receptor and high affinity immunoglobulin epsilon receptor signal transduction pathways. It also negatively regulates insulin-like growth factor 1 signaling during muscle atrophy caused by unloading and is involved in EGFR ubiquitination and internalization. Diseases associated with defects in Cbl-b include: multiple sclerosis, autoimmune diseases, including type 1 diabetes, and a craniofacial phenotype. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043 222 KNWTYLAVTHPGYMAFLTYDEVKARLQVYVNKPGSYIFRLSCTRLGQWAIGYVTADRSILQTIPQNKSLFQALVDGHKEG 301
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....
gi 2547015043 302 FYLYPDGKNVNPDL 315
Cdd:cd09920    81 FYLYPDGRLDNPDL 94

CBL proto-oncogene N-terminus, EF hand-like domain; Cbl is an adaptor protein that binds EGF receptors (or other tyrosine kinases) and SH3 domains, functioning as a negative regulator of many signaling pathways. The N-terminal domain is evolutionarily conserved, and is known to bind to phosphorylated tyrosine residues. The so called N-terminal domain is actually 3 structural domains, of which this is the central EF hand domain.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043 145 YQLSKQEAQVFWRGTWRERSLVPWSEFQKGLQQVHSVDSGPMAVALKSTIDLTCSGHISIFEFDIFTRLFQPWPTLLKNW 224
Cdd:pfam02761   1 FRITKSEAAEFWKKSFGKRTIVPWKEFRTALQQVHGIESGLEAMALKSTIDLTCNDHISIFEFDVFTRLFQPWSTLLRNW 80

                  ....
gi 2547015043 225 TYLA 228
Cdd:pfam02761  81 NLLA 84

cellulose synthase

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043  345 QLCKICAEN-------NKDVQIRPCGHLLCRECLKSWQLSKSPTCPFCRQTIWGHedvevspysskEGSPTTKDESDEGD 417
Cdd:PLN02400    37 QICQICGDDvgvtetgDVFVACNECAFPVCRPCYEYERKDGTQCCPQCKTRYRRH-----------KGSPRVEGDEDEDD 105

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043  418 LEDVDMVL----------------------------QQLMLMRQTQARAG--PVSSPNPDSVLQTP----PVPPRLDLLP 463
Cdd:PLN02400   106 VDDLENEFnyaqgngkarhqwqgedielssssrhesQPIPLLTHGQPVSGeiPCATPDNQSVRTTSgplgPAERNANSSP 185

                          170
                   ....*....|....*..
gi 2547015043  464 QRPPALPLPdYQTVSPS 480
Cdd:PLN02400   186 YIDPRQPVP-VRIVDPS 201

Src homology 2 (SH2) domain found in the Cbl-b TKB domain; SH2 found in the Cbl-b TKB domain. The Cbl (for Casitas B-lineage lymphoma) family of E3 ubiquitin ligases contains three members Cbl, Cbl-b and Cbl-c. The founding member Cbl was discovered first as the oncogenic protein v-Cbl, a Gag-fusion transforming protein of Cas NS-1 retrovirus, which causes pre- and pro-B lymphomas in mice. The N-terminus of the Cbl proteins is composed of a tyrosine kinase-binding (TKB) domain, also called phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. In addition, Cbl and Cbl-b contain a leucine zipper motif and a proline-rich domain in the C-terminus. The TKB domain consists of a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. Cbl-b plays a role in early hematopoietic development and is a negative regulator of T-cell receptor, B-cell receptor and high affinity immunoglobulin epsilon receptor signal transduction pathways. It also negatively regulates insulin-like growth factor 1 signaling during muscle atrophy caused by unloading and is involved in EGFR ubiquitination and internalization. Diseases associated with defects in Cbl-b include: multiple sclerosis, autoimmune diseases, including type 1 diabetes, and a craniofacial phenotype. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043 222 KNWTYLAVTHPGYMAFLTYDEVKARLQVYVNKPGSYIFRLSCTRLGQWAIGYVTADRSILQTIPQNKSLFQALVDGHKEG 301
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....
gi 2547015043 302 FYLYPDGKNVNPDL 315
Cdd:cd09920    81 FYLYPDGRLDNPDL 94

CBL proto-oncogene N-terminal domain 1; Cbl is an adaptor protein that binds EGF receptors (or other tyrosine kinases) and SH3 domains, functioning as a negative regulator of many signaling pathways. The N-terminal domain is evolutionarily conserved, and is known to bind to phosphorylated tyrosine residues. Cbl_N is comprised of 3 structural domains of which this is the first - a four helix bundle.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043  18 RSLEKALQGITKLQQLVCQPQVALRNSPPYLPSLLPCIYQHLSLIREHYGAGLAKVWESDFFRVFILNLLEKIKQTTRLF 97
Cdd:pfam02262   4 RTLDKAVKLLDKLVKLCQDPRLNLKNSPPYLLDLLPDTYQHLRLVAEKYRGRLDALGENEYLRIYLANLLAKCKQAAKLF 83

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2547015043  98 RRGKDKeeILLEGSAARRNLTKLSLIFSHMLAELQAVFPNGV 139
Cdd:pfam02262  84 KEGKEK--MFDEGSRYRRQLTKLSLIFSHMLAELKALFPDGK 123

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl and similar proteins; Cbl, also known as Casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55 (RNF55), or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinase signaling. It contains a tyrosine kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline-rich domain, a C3HC4-type RING-HC finger, and an ubiquitin-associated (UBA) domain. TKB is responsible for the interactions with many tyrosine kinases, such as the colony-stimulating factor-1 (CSF-1) receptor, Syk/ZAP-70, and Src-family of protein tyrosine kinases. The proline-rich domain can recruit proteins with a SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through the RING-HC finger.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2547015043 324 RNRIKVSQEQFELYSQVESTFQLCKICAENNKDVQIRPCGHLLCRECLKSWQLSKSPTCPFCRQTIWGHEDVEVSPY 400
Cdd:cd16708     1 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 77

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 2547015043  347 CKICAENN-KDVQIRPCGHLLCRECLKSWQLSKSPTCPFC 385
Cdd:smart00184   1 CPICLEEYlKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

cellulose synthase

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043  345 QLCKICAEN-------NKDVQIRPCGHLLCRECLKSWQLSKSPTCPFCRQTIWGHedvevspysskEGSPTTKDESDEGD 417
Cdd:PLN02400    37 QICQICGDDvgvtetgDVFVACNECAFPVCRPCYEYERKDGTQCCPQCKTRYRRH-----------KGSPRVEGDEDEDD 105

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043  418 LEDVDMVL----------------------------QQLMLMRQTQARAG--PVSSPNPDSVLQTP----PVPPRLDLLP 463
Cdd:PLN02400   106 VDDLENEFnyaqgngkarhqwqgedielssssrhesQPIPLLTHGQPVSGeiPCATPDNQSVRTTSgplgPAERNANSSP 185

                          170
                   ....*....|....*..
gi 2547015043  464 QRPPALPLPdYQTVSPS 480
Cdd:PLN02400   186 YIDPRQPVP-VRIVDPS 201

N1R/p28-like protein; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2547015043 347 CKICAEN--NKDVQ------IRPCGHLLCRECLKSWQLSKSpTCPFCRQT 388
Cdd:PHA02929  177 CAICMEKvyDKEIKnmyfgiLSNCNHVFCIECIDIWKKEKN-TCPVCRTP 225

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043 393 EDVEVSPYSSKEGSPTTKDESDEGDLEDVDMVLQQLMLMRQTQARAGPVSSPNPDSVLQTP---PVPPRLDLLPQRPPAL 469
Cdd:pfam03154 135 KDIDQDNRSTSPSIPSPQDNESDSDSSAQQQILQTQPPVLQAQSGAASPPSPPPPGTTQAAtagPTPSAPSVPPQGSPAT 214

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2547015043 470 PLPDYQTVSPSAHWIRDRPLPSL-PQELPPSIPA 502
Cdd:pfam03154 215 SQPPNQTQSTAAPHTLIQQTPTLhPQRLPSPHPP 248

Src homology 2 (SH2) domain found in the Cbl-b TKB domain; SH2 found in the Cbl-b TKB domain. The Cbl (for Casitas B-lineage lymphoma) family of E3 ubiquitin ligases contains three members Cbl, Cbl-b and Cbl-c. The founding member Cbl was discovered first as the oncogenic protein v-Cbl, a Gag-fusion transforming protein of Cas NS-1 retrovirus, which causes pre- and pro-B lymphomas in mice. The N-terminus of the Cbl proteins is composed of a tyrosine kinase-binding (TKB) domain, also called phosphotyrosine binding (PTB) domain, a short linker region and the RING-type zinc finger. In addition, Cbl and Cbl-b contain a leucine zipper motif and a proline-rich domain in the C-terminus. The TKB domain consists of a four-helix bundle (4H), a calcium-binding EF hand and a divergent SH2 domain. Cbl-b plays a role in early hematopoietic development and is a negative regulator of T-cell receptor, B-cell receptor and high affinity immunoglobulin epsilon receptor signal transduction pathways. It also negatively regulates insulin-like growth factor 1 signaling during muscle atrophy caused by unloading and is involved in EGFR ubiquitination and internalization. Diseases associated with defects in Cbl-b include: multiple sclerosis, autoimmune diseases, including type 1 diabetes, and a craniofacial phenotype. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043 222 KNWTYLAVTHPGYMAFLTYDEVKARLQVYVNKPGSYIFRLSCTRLGQWAIGYVTADRSILQTIPQNKSLFQALVDGHKEG 301
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....
gi 2547015043 302 FYLYPDGKNVNPDL 315
Cdd:cd09920    81 FYLYPDGRLDNPDL 94

CBL proto-oncogene N-terminal domain 1; Cbl is an adaptor protein that binds EGF receptors (or other tyrosine kinases) and SH3 domains, functioning as a negative regulator of many signaling pathways. The N-terminal domain is evolutionarily conserved, and is known to bind to phosphorylated tyrosine residues. Cbl_N is comprised of 3 structural domains of which this is the first - a four helix bundle.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2547015043  18 RSLEKALQGITKLQQLVCQPQVALRNSPPYLPSLLPCIYQHLSLIREHYGAGLAKVWESDFFRVFILNLLEKIKQTTRLF 97
Cdd:pfam02262   4 RTLDKAVKLLDKLVKLCQDPRLNLKNSPPYLLDLLPDTYQHLRLVAEKYRGRLDALGENEYLRIYLANLLAKCKQAAKLF 83

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2547015043  98 RRGKDKeeILLEGSAARRNLTKLSLIFSHMLAELQAVFPNGV 139
Cdd:pfam02262  84 KEGKEK--MFDEGSRYRRQLTKLSLIFSHMLAELKALFPDGK 123

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl and similar proteins; Cbl, also known as Casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55 (RNF55), or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinase signaling. It contains a tyrosine kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline-rich domain, a C3HC4-type RING-HC finger, and an ubiquitin-associated (UBA) domain. TKB is responsible for the interactions with many tyrosine kinases, such as the colony-stimulating factor-1 (CSF-1) receptor, Syk/ZAP-70, and Src-family of protein tyrosine kinases. The proline-rich domain can recruit proteins with a SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through the RING-HC finger.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2547015043 324 RNRIKVSQEQFELYSQVESTFQLCKICAENNKDVQIRPCGHLLCRECLKSWQLSKSPTCPFCRQTIWGHEDVEVSPY 400
Cdd:cd16708     1 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 77

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-c and similar proteins; Cbl-c, also known as RING finger protein 57 (RNF57), SH3-binding protein Cbl-3, SH3-binding protein Cbl-c, or signal transduction protein Cbl-c, is an E3 ubiquitin-protein ligase expressed exclusively in epithelial cells. It contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a C3HC4-type RING-HC finger, and a short proline-rich region, but lacks the ubiquitin-associated (UBA) leucine zipper motif that are present in Cbl and Cbl-b. Cbl-c acts as a regulator of epidermal growth factor receptor (EGFR)-mediated signal transduction. It also suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Moreover, Cbl-c ubiquitinates and downregulates RETMEN2A and implicates Enigma (PDLIM7) as a positive regulator of RETMEN2A by blocking Cbl-mediated ubiquitination and degradation. The ubiquitin ligase activity of Cbl-c is increased via the interaction of its RING-HC finger domain with a LIM domain of the paxillin homolog, hydrogen peroxide induced construct 5 (Hic-5).

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2547015043 332 EQFELYSQVESTFQLCKICAENNKDVQIRPCGHLLCRECLKSWQLSKSPTCPFCRQTIWGHEDV 395
Cdd:cd16710     1 EQLQLYQAMNSTFELCKICAERDKDVRIEPCGHLLCSCCLAAWQHSDSQTCPFCRCEIKGREAV 64

Prokaryotic RING finger family 4; RING finger family domain found sporadically in bacteria. The finger is fused to an N-terminal alpha-helical domain, ROT/Trove-like repeats and a C-terminal TerD domain. The architecture suggests a possible role in an RNA-processing complex.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSWQLSkspTCPFCRQTIWGH 392
Cdd:pfam14447   1 CVLCGRNGTVHALIPCGHLVCRDCFDGSDFS---ACPICRRRIDAD 43

HC subclass of RING (RING-HC) finger and its variants; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers. Some have a different Cys/His pattern. Some lack a single Cys or His residue at typical Zn ligand positions, especially, the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can chelate Zn in a RING finger as well. This family corresponds to the HC subclass of RING (RING-HC) fingers that are characterized by containing C3HC4-type canonical RING-HC fingers or noncanonical RING-HC finger variants, including C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type modified RING-HC fingers. The canonical RING-HC finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-HC fingers can be found in a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle, and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enables efficient transfer of ubiquitin from E2 to the substrates.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSWQLSKSPTCPFC 385
Cdd:cd16449     3 CPICLERLKDPVLLPCGHVFCRECIRRLLESGSIKCPIC 41

Zinc finger, C3HC4 type (RING finger); The C3HC4 type zinc-finger (RING finger) is a cysteine-rich domain of 40 to 60 residues that coordinates two zinc ions, and has the consensus sequence: C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-C-X2-C-X(4-48)-C-X2-C where X is any amino acid. Many proteins containing a RING finger play a key role in the ubiquitination pathway.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2547015043 347 CKICAENNKD-VQIRPCGHLLCRECLKSWQLSKSPTCPFC 385
Cdd:pfam00097   1 CPICLEEPKDpVTLLPCGHLFCSKCIRSWLESGNVTCPLC 40

RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2547015043 347 CKICAENNKD---VQIRPCGHLLCRECLKSWQLSKSPTCPFC 385
Cdd:cd00162     1 CPICREEMNDrrpVVLLSCGHTFSRSAIARWLEGSKQKCPFC 42

RING finger, HC subclass, found in peroxin-10 (PEX10) and similar proteins; PEX10, also known as peroxisome biogenesis factor 10, peroxisomal biogenesis factor 10, peroxisome assembly protein 10, or RING finger protein 69 (RNF69), is an integral peroxisomal membrane protein with two transmembrane regions and a C3HC4-type RING-HC finger within its cytoplasmically exposed C-terminus. It plays an essential role in peroxisome assembly, import of target substrates, and recycling or degradation of protein complexes and amino acids. It is an essential component of the spinal locomotor circuit, and thus its mutations may be involved in peroxisomal biogenesis disorders (PBD). Mutations in human PEX10 also result in autosomal recessive ataxia. Moreover, PEX10 functions as an E3-ubiquitin ligase with an E2, UBCH5C. It mono- or poly-ubiquitinates PEX5, a key player in peroxisomal matrix protein import, in a UBC4-dependent manner, to control PEX5 receptor recycling or degradation. It also links the E2 ubiquitin conjugating enzyme PEX4 to the protein import machinery of the peroxisome.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSWqLSKSPTCPFCRQTI 389
Cdd:cd16527     3 CSLCLEERRHPTATPCGHLFCWSCITEW-CNEKPECPLCREPF 44

RING finger, HC subclass, found in Arabidopsis thaliana protein XB3 homolog 5 (XBAT35) and similar proteins; XBAT35, also known as ankyrin repeat domain and RING finger-containing protein XBAT35, or RING-type E3 ubiquitin transferase XBAT35, has no E3 ubiquitin-protein ligase activity observed when associated with the E2 enzyme UBC8 in vitro. It contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2547015043 347 CKICAENNKDVQIRPCGHL-LCRECLKSWQlSKSPTCPFCRQTI 389
Cdd:cd23129     5 CVVCMDAPRDAVCVPCGHVaGCMSCLKALM-QSSPLCPICRAPV 47

RING finger, HC subclass, found in mind bomb MIB1, MIB2, RGLG1, RGLG2, and similar proteins; MIBs are large, multi-domain E3 ubiquitin-protein ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. They are also responsible for TBK1 K63-linked ubiquitination and activation, promoting interferon production and controlling antiviral immunity. Moreover, MIBs selectively control responses to cytosolic RNA and regulate type I interferon transcription. Both MIB1 and MIB2 have similar domain architectures, which consist of two Mib-Herc2 domains flanking a ZZ zinc finger, a REP region including two tandem Mib repeats, an ANK region that spans ankyrin repeats, and a RNG region, where MIB1 and MIB2 contain three and two C3HC4-type RING-HC fingers, respectively. This model corresponds to the third RING-HC finger of MIB1, as well as the second RING-HC finger of MIB2. In addition to MIB1 and MIB2, the RING-HC fingers of RING domain ligase RGLG1, RGLG2 and similar proteins from plant are also included in this model. RGLG1 is a ubiquitously expressed E3 ubiquitin-protein ligase that interacts with UBC13 and, together with UBC13, catalyzes the formation of K63-linked polyubiquitin chains, which is involved in DNA damage repair. RGLG1 mediates the formation of canonical, K48-linked polyubiquitin chains that target proteins for degradation. It also regulates apical dominance by acting on the auxin transport proteins abundance. RGLG1 has overlapping functions with its closest sequelog, RGLG2. They both function as RING E3 ligases that interact with ethylene response factor 53 (ERF53) in the nucleus and negatively regulate the plant drought stress response. All RGLG proteins contain a Von Willebrand factor type A (vWA) domain and a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2547015043 345 QLCKICAENNKDVqIRPCGHLLCREClkSWQLSKsptCPFCRQTI 389
Cdd:cd16520     1 ILCPICMERKKNV-VFLCGHGTCQKC--AEKLKK---CPICRKPI 39

RING finger, HC subclass, found in inhibitor of apoptosis proteins (IAPs); IAPs are frequently overexpressed in cancer and associated with tumor cell survival, chemoresistance, disease progression, and poor prognosis. They function primarily as negative regulators of cell death. They regulate caspases and apoptosis through the inhibition of specific members of the caspase family of cysteine proteases. In addition, IAPs has been implicated in a multitude of other cellular processes, including inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis. IAPs in this family includes cellular inhibitor of apoptosis protein c-IAP1 (BIRC2) and c-IAP2 (BIRC3), XIAP (BIRC4), BIRC7, and BIRC8, all of which contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. The UBA domain is only absent in mammalian homologs of BIRC7. Moreover, c-IAPs contains an additional caspase activation and recruitment domain (CARD) between the UBA and C3HC4-type RING-HC domains. The CARD domain may serve as a protein interaction surface.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2547015043 345 QLCKICAENNKDVQIRPCGHLL-CRECLKSWQlskspTCPFCRQ 387
Cdd:cd16510     2 KLCKICMDREVNIVFLPCGHLVtCAQCAASLR-----KCPICRT 40

Modified RING finger, HC subclass (C3HC5-type), found in RING finger proteins, RNF26, RNF197 (CGRRF1), RNF156 (MGRN1), RNF157 and similar proteins; This subfamily corresponds to a group of RING finger proteins containing a modified C3HC5-type RING-HC finger, which is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain. Cell growth regulator with RING finger domain protein 1 (CGRRF1), also known as cell growth regulatory gene 19 protein (CGR19) or RING finger protein 197 (RNF197), functions as a novel biomarker to monitor endometrial sensitivity and response to insulin-sensitizing drugs, such as metformin, in the context of obesity. RNF26 is an E3 ubiquitin ligase that temporally regulates virus-triggered type I interferon induction by increasing the stability of Mediator of IRF3 activation, MITA, also known as STING, through K11-linked polyubiquitination after viral infection and promoting degradation of IRF3, another important component required for virus-triggered interferon induction. Mahogunin ring finger-1 (MGRN1), also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase MGRN1. In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2547015043 345 QLCKICAENNKDVQIRPCGHL-LCRECLKSwqlSKSPTCPFCR 386
Cdd:cd16649     1 GLCVVCLENPASVLLLPCRHLcLCEVCAKG---LRGKTCPICR 40

zinc-RING finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2547015043 347 CKICAE---NNKDVQIRPCGHLLCRECLKswQLSKSPTCPFCRQ 387
Cdd:pfam14634   2 CNKCFKelsKTRPFYLTSCGHIFCEECLT--RLLQERQCPICKK 43

RING finger, H2 subclass, found in Tetratricopeptide repeat protein 3 (TTC3) and similar proteins; TTC3, also known as protein DCRR1, TPR repeat protein D, TPR repeat protein 3, or RING finger protein 105 (RNF105), is an E3 ubiquitin-protein ligase encoded by a gene within the Down syndrome (DS) critical region on chromosome 21. It affects differentiation and Golgi compactness in neurons through specific actin-regulating pathways. It inhibits the neuronal-like differentiation of pheocromocytoma cells by activating RhoA and by binding to Citron proteins. TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus. It contains four N-terminal TPR motifs, a potential coiled-coil region and a Citron binding region in the central part, and a C-terminal C3H2C2-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2547015043 346 LCKICAENNKDVQIR--PCGHLLCRECLKSWqLSKSPTCPFCRQTI 389
Cdd:cd16481     1 PCIICHDDLKPDQLAklECGHIFHKECIKQW-LKEQSTCPTCRVHV 45

RING finger, HC subclass, found in RING finger protein 185 (RNF185) and similar proteins; RNF185 is an E3 ubiquitin-protein ligase of endoplasmic reticulum-associated degradation (ERAD) that targets cystic fibrosis transmembrane conductance regulator (CFTR). It controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical ERAD model substrates. It also negatively regulates osteogenic differentiation by targeting dishevelled2 (Dvl2), a key mediator of the Wnt signaling pathway, for degradation. Moreover, RNF185 regulates selective mitochondrial autophagy through interaction with the Bcl-2 family protein BNIP1. It also plays an important role in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. RNF185 contains a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSWQLSK--SPTCPFCRQTI 389
Cdd:cd16744     3 CNICLDTAKDAVVSLCGHLFCWPCLHQWLETRpnRQVCPVCKAGI 47

RING finger, HC subclass, found in bifunctional apoptosis regulator (BAR); BAR, also known as RING finger protein 47, was originally identified as an inhibitor of Bax-induced apoptosis. It participates in the block of apoptosis induced by TNF-family death receptors (extrinsic pathway) and mitochondria-dependent apoptosis (intrinsic pathway). BAR is predominantly expressed by neurons in the central nervous system and is involved in the regulation of neuronal survival. It is an endoplasmic reticulum (ER)-associated RING-type E3 ubiquitin ligase that interacts with BI-1 protein and post-translationally regulates its stability, as well as functioning in ER stress. BAR contains an N-terminal C3HC4-type RING-HC finger, a SAM domain, a coiled-coil domain, and a C-terminal transmembrane (TM) domain. This model corresponds to the RING-HC finger responsible for the binding of ubiquitin conjugating enzymes (E2s).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2547015043 346 LCKICAENNKDVQIRPCGHLLCRECLKSWQL-SKSPTCPFCRQTIWGH 392
Cdd:cd16497     3 LCHCCYDLLVNPTTLNCGHSFCRHCLALWWKsSKKTECPECRQKWEGF 50

RING finger, HC subclass, found in RING finger protein 138 (RNF138) and similar proteins; RNF138, also known as Nemo-like kinase-associated RING finger protein (NARF) or NLK-associated RING finger protein, is an E3 ubiquitin-protein ligase that plays an important role in glioma cell proliferation, apoptosis, and cell cycle. It specifically cooperates with the E2 conjugating enzyme E2-25K (Hip-2/UbcH1), regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF), and further suppresses Wnt-beta-catenin signaling. RNF138, together with three closely related proteins: RNF114, RNF125 and RNF166, forms a novel family of ubiquitin ligases with a C3HC4-type RING-HC finger, a C2HC-, and two C2H2-type zinc fingers, as well as a ubiquitin interacting motif (UIM).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 2547015043 346 LCKICAENNKD-VQIRPCGHLLCRECLKSWQLSKSPTCPFCRQTIWGHE 393
Cdd:cd16544     4 TCPVCQEVLKDpVELPPCRHIFCKACILLALRSSGARCPLCRGPVGKTE 52

RING finger, HC subclass, found in RING finger and transmembrane domain-containing protein RNFT1, RNFT2, and similar proteins; Both RNFT1 and RNFT2 are multi-pass membrane proteins containing a C3HC4-type RING-HC finger. Their biological roles remain unclear.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 2547015043 346 LCKICAENNKDVQIRPCGHLLCRECLKSWqLSKSPTCPFCR 386
Cdd:cd16532     2 ICPICQDEFKDPVVLRCKHIFCEDCVSEW-FERERTCPLCR 41

RING finger, HC subclass, found in RING finger protein RNF5, RNF185 and similar proteins; RNF5 and RNF185 are E3 ubiquitin-protein ligases that are anchored to the outer membrane of the endoplasmic reticulum (ER). RNF5 acts at early stages of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) biosynthesis, and functions as a target for therapeutic modalities to antagonize mutant CFTR proteins in CF patients carrying the F508del allele. RNF185 controls the degradation of CFTR and CFTR F508del allele in a RING- and proteasome-dependent manner, but does not control that of other classical endoplasmic reticulum-associated degradation (ERAD) model substrates. Moreover, both RNF5 and RNF185 play important roles in cell adhesion and migration through the modulation of cell migration by ubiquitinating paxillin. Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) are also included in this family. They possess E3 ubiquitin-protein ligase activity and may play a role in the growth and development of Arabidopsis. All members of this family contain a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSW--QLSKSPTCPFCR 386
Cdd:cd16534     3 CNICLDTASDPVVTMCGHLFCWPCLYQWleTRPDRQTCPVCK 44

RING finger, HC subclass, found in helicase-like transcription factor (HLTF) and similar proteins; HLTF, also known as DNA-binding protein/plasminogen activator inhibitor 1 regulator, HIP116, RING finger protein 80, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 3, or sucrose nonfermenting protein 2-like 3, is a yeast RAD5 homolog found in mammals. It has both E3 ubiquitin ligase and DNA helicase activities, and plays a pivotal role in the template-switching pathway of DNA damage tolerance. It is involved in Lys-63-linked poly-ubiquitination of proliferating cell nuclear antigen (PCNA) at Lys-164 and in the regulation of DNA damage tolerance. It shows double-stranded DNA translocase activity with 3'-5' polarity, thereby facilitating regression of the replication fork. HLTF contains an N-terminal HIRAN (HIP116 and RAD5 N-terminal) domain, a SWI/SNF helicase domain that is divided into N- and C-terminal parts by an insertion of a C3HC4-type RING-HC finger involved in the poly-ubiquitination of PCNA.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSWQLSKSPTCPFCRQTI 389
Cdd:cd16509     6 CAICLDSLTNPVITPCAHVFCRRCICEVIQREKAKCPMCRAPL 48

Modified RING finger, HC subclass (C3HC5-type), found in mitochondrial-anchored protein ligase (MAPL) and similar proteins; MAPL, also known as MULAN, mitochondrial ubiquitin ligase activator of NFKB 1, E3 SUMO-protein ligase MUL1, E3 ubiquitin-protein ligase MUL1, growth inhibition and death E3 ligase (GIDE), putative NF-kappa-B-activating protein 266, or RING finger protein 218 (RNF218), is a multifunctional mitochondrial outer membrane protein involved in several processes specific to metazoan (multicellular animal) cells, such as NF-kappaB activation, innate immunity and antiviral signaling, suppression of PINK1/parkin defects, mitophagy in skeletal muscle, and caspase-dependent apoptosis. MAPL contains a unique BAM (beside a membrane)/GIDE (growth inhibition death E3 ligase) domain and a C-terminal modified cytosolic C3HC5-type RING-HC finger which is distinguished from typical C3HC4-type RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2547015043 347 CKICAENNKDVQIRPCGHL-LCRECLKSwqLSKSPTCPFCRQTI 389
Cdd:cd16648     4 CVICLSNPRSCVFLECGHVcSCIECYEA--LPSPKKCPICRSFI 45

RING finger, H2 subclass, found in the PA-TM-RING ubiquitin ligase family; The PA-TM-RING family represents a group of transmembrane-type E3 ubiquitin ligases, which has been characterized by an N-terminal transient signal peptide, a PA (protease-associated) domain, a TM (transmembrane) domain, as well as a C-terminal C3H2C3-type RING-H2 finger domain. It includes RNF13, RNF167, ZNRF4 (zinc and RING finger 4), GRAIL (gene related to anergy in lymphocytes)/RNF128, RNF130, RNF133, RNF148, RNF149 and RNF150 (which are more closely related), as well as RNF43 and ZNRF3, which have substantially longer C-terminal tail extensions compared with the others. PA-TM-RING proteins are expressed at low levels in all mammalian tissues and species, but they are not present in yeast. They play a common regulatory role in intracellular trafficking/sorting, suggesting that abrogation of their function may result in dysregulation of cellular signaling events in cancer.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2547015043 347 CKICAEN---NKDVQIRPCGHLLCRECLKSWqLSKSPTCPFCR 386
Cdd:cd16454     2 CAICLEEfkeGEKVRVLPCNHLFHKDCIDPW-LEQHNTCPLCR 43

RING finger, H2 subclass, found in protein E3 ubiquitin-protein ligase Praja-1, Praja-2, and similar proteins; This family includes two highly similar E3 ubiquitin-protein ligases, Praja-1 and Praja-2. Praja-1, also known as RING finger protein 70, is a RING-H2 finger ubiquitin ligase encoded by gene PJA1, a novel human X chromosome gene abundantly expressed in the brain. It has been implicated in bone and liver development, as well as memory formation and X-linked mental retardation (MRX). Praja-1 interacts with and activates the ubiquitin-conjugating enzyme UbcH5B, and shows E2-dependent E3 ubiquitin ligase activity. It is a 3-deazaneplanocin A (DZNep)-induced ubiquitin ligase that directly ubiquitinates individual polycomb repressive complex 2 (PRC2) subunits in a cell free system, which leads to their proteasomal degradation. It also plays an important role in neuronal plasticity, which is the basis for learning and memory. Moreover, Praja-1 ubiquitinates embryonic liver fodrin (ELF) and Smad3, but not Smad4, in a transforming growth factor-beta (TGF-beta)-dependent manner. It controls ELF abundance through ubiquitin-mediated degradation, and further regulates TGF-beta signaling, which plays a key role in the suppression of gastric carcinoma. Praja-1 also regulates the transcription function of the homeodomain protein Dlx5 by controlling the stability of Dlxin-1, via a ubiquitin-dependent degradation pathway. Praja-2, also known as RING finger protein 131, NEURODAP1, or KIAA0438, is an E2-dependent E3 ubiquitin ligase that interacts with and activates the ubiquitin-conjugating enzyme UbcH5B. It functions as an A-kinase anchoring protein (AKAP)-like E3 ubiquitin ligase that plays a critical role in controlling cyclic AMP (cAMP)-dependent PKA activity and pro-survival signaling, and further promotes cell proliferation and growth. Praja-2 is also involved in protein sorting at the postsynaptic density region of axosomatic synapses and possibly plays a role in synaptic communication and plasticity. Together with the AMPK-related kinase SIK2 and the CDK5 activator CDK5R1/p35, it forms a SIK2-p35-PJA2 complex that plays an essential role for glucose homeostasis in pancreatic beta cell functional compensation. Praja-2 ubiquitylates and degrades Mob, a core component of NDR/LATS kinase and a positive regulator of the tumor-suppressor Hippo signaling. Both Praja-1 and Praja-2 contain a potential nuclear localization signal (NLS) and a C-terminal C3H2C3-type RING-H2 motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2547015043 347 CKIC-AENNKD--VQIRPCGHLLCRECLKSWqLSKSPTCPFCRQTI 389
Cdd:cd16465     2 CPICcSEYVKDeiATELPCHHLFHKPCITAW-LQKSGTCPVCRHVL 46

RING finger, HC subclass, found in Equid alphaherpesvirus 1 (Equine herpesvirus 1/EHV-1) regulatory protein and similar proteins; EHV-1 regulatory protein belongs to the Vmw110 (IPC0) protein family. It contains a typical C3HC4-type RING-HC finger and binds zinc stably.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2547015043 347 CKICAEN-NKDVQIRPCGHLLCRECLKSWqLSKSPTCPFCRQ 387
Cdd:cd23130     3 CPICLDDpEDEAITLPCLHQFCYTCILRW-LQTSPTCPLCKT 43

RING finger, HC subclass, found in RING finger protein 123 (RNF123) and similar proteins; RNF123, also known as Kip1 ubiquitination-promoting complex protein 1 (KPC1), is an E3 ubiquitin-protein ligase that mediates ubiquitination and proteasomal processing of the nuclear factor-kappaB 1 (NF-kappaB1) precursor p105 to the p50 active subunit that restricts tumor growth. It also regulates degradation of heterochromatin protein 1alpha (HP1alpha) and 1beta (HP1beta) in lamin A/C knock-down cells. Moreover, RNF123, together with Kip1 ubiquitylation-promoting complex 2 (KPC2), forms the Kip1 ubiquitination-promoting complex (KPC), acting as a cytoplasmic ubiquitin ligase that regulates degradation of the cyclin-dependent kinase inhibitor p27 (Kip1) at the G1 phase of the cell cycle. RNF123 may also function as a clinically relevant, peripheral state marker of depression. RNF123 contains a C3HC4-type RING-HC finger at the C-terminus.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2547015043 345 QLCKICAENNKDVQIRPCGHLLCRECLkSWQLSKSPTCPFCRQTI 389
Cdd:cd16541     1 DLCPICYAHPIDAVFLPCGHKSCRSCI-NRHLMNNKECFFCKATI 44

RING finger, HC subclass, found in Saccharomyces cerevisiae increased recombination centers protein 20 (IRC20) and similar proteins; IRC20 is an uncharacterized ATP-dependent helicase that is probably involved in a pathway contributing to genomic integrity. IRC20 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSWQLSKSpTCPFCR 386
Cdd:cd23135     6 CSICFSEIRSGAILKCGHFFCLSCIASWLREKS-TCPLCK 44

RING-type zinc-finger; This zinc-finger is a typical RING-type of plant ubiquitin ligases.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 2547015043 347 CKICAENNKDVQIrPCGHLLCRECL--KSWQLSKSPTCP 383
Cdd:pfam13445   1 CPICLELFTDPVL-PCGHTFCRECLeeMSQKKGGKFKCP 38

RING finger, HC subclass, found in topoisomerase I-binding arginine/serine-rich protein (Topors) and similar proteins; Topors, also known as topoisomerase I-binding RING finger protein, tumor suppressor p53- binding protein 3, or p53-binding protein 3 (p53BP3), is a ubiquitously expressed nuclear E3 ubiquitin-protein ligase that can ligate both ubiquitin and small ubiquitin-like modifier (SUMO) to substrate proteins in the nucleus. It contains an N-terminal C3HC4-type RING-HC finger which ligates ubiquitin to its target proteins including DNA topoisomerase I, p53, NKX3.1, H2AX, and the AAV-2 Rep78/68 proteins. As a RING-dependent E3 ubiquitin ligase, Topors works with the E2 enzymes UbcH5a, UbcH5c, and UbcH6, but not with UbcH7, CDC34, or UbcH2b. Topors acts as a tumor suppressor in various malignancies. It regulates p53 modification, suggesting it may be responsible for astrocyte elevated gene-1 (AEG-1, also known as metadherin, or LYRIC) ubiquitin modification. Plk1-mediated phosphorylation of Topors inhibits Topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation. It also functions as a negative regulator of the prostate tumor suppressor NKX3.1. Moreover, Topors is associated with promyelocytic leukemia nuclear bodies, and may be involved in the cellular response to camptothecin. It also plays a key role in the turnover of H2AX protein, discriminating the type of DNA damaging stress. Furthermore, Topors is a cilia-centrosomal protein associated with autosomal dominant retinal degeneration. Mutations in TOPORS cause autosomal dominant retinitis pigmentosa (adRP).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2547015043 345 QLCKICAENNKD--VQIRPCGHLLCRECLKSWqlSK-SPTCPFCRQ 387
Cdd:cd16574     2 SSCPICLDRFENekAFLDGCFHAFCFTCILEW--SKvKNECPLCKQ 45

RING finger, HC subclass, found in Arabidopsis thaliana RING membrane-anchor proteins (AtRMAs) and similar proteins; AtRMAs, including AtRma1, AtRma2, and AtRma3, are endoplasmic reticulum (ER)-localized Arabidopsis homologs of human outer membrane of the ER-anchor E3 ubiquitin-protein ligase, RING finger protein 5 (RNF5). AtRMAs possess E3 ubiquitin ligase activity, and may play a role in the growth and development of Arabidopsis. The AtRMA1 and AtRMA3 genes are predominantly expressed in major tissues, such as cotyledons, leaves, shoot-root junction, roots, and anthers, while AtRMA2 expression is restricted to the root tips and leaf hydathodes. AtRma1 probably functions with the Ubc4/5 subfamily of E2. AtRma2 is likely involved in the cellular regulation of ABP1 expression levels through interacting with auxin binding protein 1 (ABP1). AtRMA proteins contain an N-terminal C3HC4-type RING-HC finger and a trans-membrane-anchoring domain in their extreme C-terminal region.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSW--QLSKSPTCPFCR 386
Cdd:cd16745     3 CNICLDLAQDPVVTLCGHLFCWPCLHKWlrRQSSQPECPVCK 44

RING finger, HC subclass, found in RNA-binding protein MEX3C; MEX3C, also known as RING finger and KH domain-containing protein 2 (RKHD2), or RING finger protein 194 (RNF194), is an RNA-binding phosphoprotein that acts as a suppressor of chromosomal instability. It functions as an ubiquitin E3 ligase responsible for the post-transcriptional, HLA-A allotype-specific regulation of MHC class I molecules (MHC-I). It also modifies retinoic acid inducible gene-1 (RIG-I) in stress granules and plays a critical role in eliciting antiviral immune responses. Moreover, MEX3C plays an essential role in normal postnatal growth via enhancing the local expression of insulin-like growth factor 1 (IGF1) in bone. It may also be involved in metabolic regulation of energy balance. MEX3C contains two K homology (KH) domains that provide RNA-binding capacity, and a C-terminal C3HC4-type RING-HC finger. Like other MEX-3 family proteins, MEX3C shuttles between the nucleus and the cytoplasm via the CRM1-dependent export pathway.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2547015043 347 CKICAENNKDVQIRPCGH-LLCRECLKSWQLSKSPTCPFCRQTI 389
Cdd:cd16722     4 CVICFENEVIAALVPCGHnLFCMECANKICEKETPSCPVCQTAV 47

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSWQLSKSP---TCPFCRQ 387
Cdd:cd16609     6 CSICLGLYQDPVTLPCQHSFCRACIEDHWRQKDEgsfSCPECRA 49

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

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gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECL-KSW--QLSKSPTCPFCRQT 388
Cdd:cd16597     8 CSICLELFKDPVTLPCGHNFCGVCIeKTWdsQHGSEYSCPQCRAT 52

Modified RING finger, HC subclass (C3HC5-type), found in mahogunin RING finger protein 1 (MGRN1), RING finger protein 157 (RNF157) and similar proteins; MGRN1, also known as RING finger protein 156 (RNF156), is a cytosolic E3 ubiquitin-protein ligase that inhibits signaling through the G protein-coupled melanocortin receptors-1 (MC1R), -2 (MC2R) and -4 (MC4R) via ubiquitylation-dependent and -independent processes. It suppresses chaperone-associated misfolded protein aggregation and toxicity. MGRN1 interacts with cytosolic prion proteins (PrPs) that are linked with neurodegeneration. It also interacts with expanded polyglutamine proteins, and suppresses misfolded polyglutamine aggregation and cytotoxicity. Moreover, MGRN1 inhibits melanocortin receptor signaling by competition with Galphas, suggesting a novel pathway for melanocortin signaling from the cell surface to the nucleus. MGRN1 also interacts with and ubiquitylates TSG101, a key component of the endosomal sorting complex required for transport (ESCRT)-I, and regulates endosomal trafficking. A null mutation in the gene encoding MGRN1 causes spongiform neurodegeneration, suggesting a link between dysregulation of endosomal trafficking and spongiform neurodegeneration. RNF157 is a cytoplasmic E3 ubiquitin ligase predominantly expressed in the brain. It is a homolog of the E3 ligase mahogunin ring finger-1 (MGRN1). In cultured neurons, it promotes neuronal survival in an E3 ligase-dependent manner. In contrast, it supports growth and maintenance of dendrites independent of its E3 ligase activity. RNF157 interacts with and ubiquitinates the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65), which regulates neuronal survival, but not dendritic growth downstream of RNF157. The nuclear localization of APBB1 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis. Both MGRN1 and RNF157 contain a modified C3HC5-type RING-HC finger, and a functionally uncharacterized region, known as domain associated with RING2 (DAR2), N-terminal to the RING finger. The C3HC5-type RING-HC finger is distinguished from typical C3HC4 RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

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gi 2547015043 346 LCKICAENNKDVQIRPCGHL-LCRECLKSWQLSkSPTCPFCR 386
Cdd:cd16789     2 ECVICLSDPRDTAVLPCRHLcLCSDCAEVLRYQ-SNKCPICR 42

RING finger, HC subclass, found in tripartite motif-containing protein 69 (TRIM69) and similar proteins; TRIM69, also known as RFP-like domain-containing protein trimless or RING finger protein 36 (RNF36), is a testis E3 ubiquitin-protein ligase that plays a specific role in apoptosis and may also play an important role in germ cell homeostasis during spermatogenesis. TRIM69 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

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gi 2547015043 347 CKICAENNKDVQIRPCGHLLCRECLKSW--QLSKSPTCPFCRQ 387
Cdd:cd16611     7 CPLCLDFFRDPVMLSCGHNFCQSCITGFweLQAEDTTCPECRE 49

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein 1A (NEURL1A) and similar proteins; NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of the Drosophila neuralized (D-neu) protein. It functions as an E3 ubiquitin-protein ligase that directly interacts with and monoubiquitinates cytoplasmic polyadenylation element-binding protein 3 (CPEB3), an RNA binding protein and a translational regulator of local protein synthesis, which facilitates hippocampal plasticity and hippocampal-dependent memory storage. It also acts as a potential tumor suppressor that causes apoptosis and downregulates Notch target genes in the medulloblastoma. NEURL1A contains two neuralized homology regions (NHRs) responsible for Neural-ligand interactions and a modified C3HC5-type RING-HC finger required for ubiquitin ligase activity. The C3HC5-type RING-HC finger is distinguished from typical C3HC4-type RING-HC finger due to the existence of the additional cysteine residue in the middle portion of the RING finger domain.

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gi 2547015043 347 CKICAENNKDVQIRPCGHL-LCRECLKSWQLSKSPTCPFCRQTI 389
Cdd:cd16785     7 CTICYENAVDTVIYTCGHMcLCYACGLRLKKMLNACCPICRRAI 50