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 2456637085 240 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 319
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 2456637085 320 FYLFPDGRNQNPDLTGL 336
Cdd:cd09920    81 FYLYPDGRLDNPDLSGA 97

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 2456637085 342 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTAWQESEGQGCPFCRCEIKGTEPIVVDPF 418
Cdd:cd16708     1 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 77

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  463 ERPPSPFSVAPqAALP------PVPPRL--------DLLQQRVANP----PGASSPGTTSKAVPGALHKDKPL--PIPPT 522
Cdd:PHA03247  2507 DAPPAPSRLAP-AILPdepvgePVHPRMltwirgleELASDDAGDPppplPPAAPPAAPDRSVPPPRPAPRPSepAVTSR 2585

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  523 LRDLPPPPPPDRPHSIGAEGRPQRRPLPCT--PGDCPSRDKPPPVPSNRQAELWPSRPMPkAPSVALSPGDPWAGRELSN 600
Cdd:PHA03247  2586 ARRPDAPPQSARPRAPVDDRGDPRGPAPPSplPPDTHAPDPPPPSPSPAANEPDPHPPPT-VPPPERPRDDPAPGRVSRP 2664

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  601 RHSLPFSLPSQMDS-------RAESHRLGSTVSL----DNPVSLNTGPPTTSECEHPKIKPSSSANAIYSLAARPLP--- 666
Cdd:PHA03247  2665 RRARRLGRAAQASSppqrprrRAARPTVGSLTSLadppPPPPTPEPAPHALVSATPLPPGPAAARQASPALPAAPAPpav 2744

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  667 --VPKLPPGEQSESDEDTEYMSPSS----LPVVPPGPAVQKPELKMPLEMTQSLRVSECEQQTEACMYEAMYNIHSQAAS 740
Cdd:PHA03247  2745 paGPATPGGPARPARPPTTAGPPAPappaAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASP 2824

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  741 SAFEAVSTSDAGdlAAASASNGPEESENEEDGYDVP----------KPPLPVATARRTLSDISNATPAFSRmslendPVT 810
Cdd:PHA03247  2825 AGPLPPPTSAQP--TAPPPPPGPPPPSLPLGGSVAPggdvrrrppsRSPAAKPAAPARPPVRRLARPAVSR------STE 2896

                          410
                   ....*....|....*..
gi 2456637085  811 GFSDGSQVPERPPKPLP 827
Cdd:PHA03247  2897 SFALPPDQPERPPQPQA 2913

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 2456637085 240 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 319
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 2456637085 320 FYLFPDGRNQNPDLTGL 336
Cdd:cd09920    81 FYLYPDGRLDNPDLSGA 97

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 2456637085 163 FRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNW 242
Cdd:pfam02761   1 FRITKSEAAEFWKKSFGKRTIVPWKEFRTALQQVHGIESGLEAMALKSTIDLTCNDHISIFEFDVFTRLFQPWSTLLRNW 80

                  ....
gi 2456637085 243 NSLA 246
Cdd:pfam02761  81 NLLA 84

UBA domain found in E3 ubiquitin-protein ligase Cbl and similar proteins; Cbl, also called casitas B-lineage lymphoma proto-oncogene, proto-oncogene c-Cbl, RING finger protein 55, or signal transduction protein Cbl, is a multi-domain protein that acts as a key negative regulator of various receptor and non-receptor tyrosine kinases signaling. It contains a tyrosine kinase-binding domain (TKB), a proline-rich domain, a RING domain, and a ubiquitin-associated (UBA) domain. The 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 SH3 domain. Moreover, Cbl functions as an E3 ubiquitin ligase that can bind ubiquitin-conjugating enzymes (E2s) through RING domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2456637085 854 LSSEIENLLSQGYSYQDIQKALLIAHNNIEMAKNILREFV 893
Cdd:cd14393     1 LSSEIENLMSQGYSYQDIQKALVIAQNNIEMAKNILREFV 40

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 2456637085  365 CKICAEN-DKDVKIEPCGHLMCTSCLTAWQESEGQGCPFC 403
Cdd:smart00184   1 CPICLEEyLKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

Ubiquitin associated domain; Present in Rad23, SNF1-like kinases. The newly-found UBA in p62 is known to bind ubiquitin.

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 2456637085  854 LSSEIENLLSQGYSYQDIQKALLIAHNNIEMAKNIL 889
Cdd:smart00165   1 DEEKIDQLLEMGFSREEALKALRAANGNVERAAEYL 36

UV excision repair protein Rad23; All proteins in this family for which functions are known are components of a multiprotein complex used for targeting nucleotide excision repair to specific parts of the genome. In humans, Rad23 complexes with the XPC protein. This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085 793 SNATPAFSRMSLENDPVTGFSDGSQVPERPPKPLPRrinSERKAGSCPPGGASSGTSASLQLSSEIENLLSQGYSYQDIQ 872
Cdd:TIGR00601  98 TPSPPASPASGMSAAPASAVEEKSPSEESATATAPE---SPSTSVPSSGSDAASTLVVGSERETTIEEIMEMGYEREEVE 174

                          90
                  ....*....|...
gi 2456637085 873 KALLIAHNNIEMA 885
Cdd:TIGR00601 175 RALRAAFNNPDRA 187

N1R/p28-like protein; Provisional

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2456637085 365 CKICAEN--DKDVK------IEPCGHLMCTSCLTAWQEsEGQGCPFCR 404
Cdd:PHA02929  177 CAICMEKvyDKEIKnmyfgiLSNCNHVFCIECIDIWKK-EKNTCPVCR 223

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 2456637085 240 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 319
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 2456637085 320 FYLFPDGRNQNPDLTGL 336
Cdd:cd09920    81 FYLYPDGRLDNPDLSGA 97

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 2456637085 163 FRITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNW 242
Cdd:pfam02761   1 FRITKSEAAEFWKKSFGKRTIVPWKEFRTALQQVHGIESGLEAMALKSTIDLTCNDHISIFEFDVFTRLFQPWSTLLRNW 80

                  ....
gi 2456637085 243 NSLA 246
Cdd:pfam02761  81 NLLA 84

RING finger, HC subclass, found in E3 ubiquitin-protein ligase Cbl-b and similar proteins; Cbl-b, also known as Casitas B-lineage lymphoma proto-oncogene b, RING finger protein 56 (RNF56), SH3-binding protein Cbl-b, or signal transduction protein Cbl-b, has been identified as a regulator of antigen-specific, T cell-intrinsic, peripheral immune tolerance, a state also known as clonal anergy. It may inhibit activation of the p85 subunit of phosphoinositide 3-kinase (PI3K), protein kinase C-theta (PKC-theta), and phospholipase C-gamma1 (PLC-gamma1) and negatively regulates T-cell receptor-induced transcription factor nuclear factor kappaB (NF-kappaB) activation. In addition, Cbl-b may target multiple signaling molecules involved in transforming growth factor (TGF)-beta-mediated transactivation pathways. Cbl-b contains a tyrosine-kinase-binding domain (TKB, also known as the phosphotyrosine binding PTB domain, is composed of a four helix-bundle, a Ca2+ binding EF-hand and a highly variant SH2 domain), a proline rich domain, a nuclear localization signal, a C3HC4-type RING-HC finger and an ubiquitin-associated (UBA) domain.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2456637085 343 DHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTAWQESEGQGCPFCRCEIKGTEPIVVDPF 418
Cdd:cd16709     1 DHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTAWQESDGQGCPFCRCEIKGTEPIIVDPF 76

RING finger, HC subclass, found in Casitas B-lineage lymphoma (Cbl) proteins; The Cbl adaptor protein family contains a small class of RING-type E3 ubiquitin ligases with oncogenic activity, which is represented by three mammalian members, c-Cbl, Cbl-b and Cbl-c, as well as two invertebrate Cbl-family proteins, D-Cbl in Drosophila and Sli-1 in C. elegans. Cbl proteins function as potent negative regulators of various signaling cascades in a wide range of cell types. They play roles in ubiquitinating activated tyrosine kinases and targeting them for degradation. D-Cbl associates with the Drosophila epidermal growth factor receptor (EGFR) and overexpression of D-Cbl in the eye of Drosophila embryos inhibits EGFR-dependent photoreceptor cell development. Sli-1 is a negative regulator of the Let-23 receptor tyrosine kinase, an EGFR homolog, in vulva development. Cbl proteins in this subfamily consist of a highly conserved N-terminal half that includes 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) and a C3HC4-type RING-HC finger, both of which are required for Cbl-mediated downregulation of RTKs, and a divergent C-terminal region.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2456637085 362 FQLCKICAENDKDVKIEPCGHLMCTSCLTAWQESEGQGCPFCR 404
Cdd:cd16502     1 FQLCKICAENDKDVRIEPCGHLLCTPCLTSWQDSDGQTCPFCR 43

UBA domain found in casitas B-lineage lymphoma (Cbl) proteins; The Cbl adaptor proteins family contains a small class of RING-type E3 ubiquitin ligases with oncogenic activity which is represented by three mammalian members, c-Cbl, Cbl-b and Cbl-3. Cbl proteins function as potent negative regulators of various signaling cascades in a wide range of cell types. They play roles in ubiquitinating the activated tyrosine kinases and targeting them for degradation. Cbl proteins in this family consists of a highly conserved N-terminal half that includes a tyrosine-kinase-binding (TKB) domain and a RING finger domain, both of which are required for Cbl-mediated downregulation of RTKs, and a C-terminal half that includes a ubiquitin-associated (UBA) domain and other protein interaction motifs. The UBA domain contains leucine/isoleucine repeats and may play a role in dimerization of Cbl proteins. In addition, although both c-Cbl and Cbl-b have the C-terminal UBA domain, only the UBA domain from Cbl-b can bind ubiquitin.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2456637085 854 LSSEIENLLSQGYSYQDIQKALLIAHNNIEMAKNILREFV 893
Cdd:cd14318     1 LLSYIAKLVGEGYSKEDVIRALGIARNNVEMARDILREFA 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 2456637085 365 CKICAENDKD---VKIEPCGHLMCTSCLTAWQESEGQGCPFC 403
Cdd:cd00162     1 CPICREEMNDrrpVVLLSCGHTFSRSAIARWLEGSKQKCPFC 42

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 2456637085  365 CKICAEN-DKDVKIEPCGHLMCTSCLTAWQESEGQGCPFC 403
Cdd:smart00184   1 CPICLEEyLKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

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 2456637085 365 CKICAENDKDVKIEPCGHLMCTSCLTAWQESEGQGCPFC 403
Cdd:cd16449     3 CPICLERLKDPVLLPCGHVFCRECIRRLLESGSIKCPIC 41

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 2456637085 363 QLCKICAENDKDVKIEPCGHL-MCTSCLtawQESEGQGCPFCR 404
Cdd:cd16649     1 GLCVVCLENPASVLLLPCRHLcLCEVCA---KGLRGKTCPICR 40

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 2456637085 365 CKICAENDKDVKIEPCGHL-MCTSCLTAWQESEGqGCPFCRCEIKGT 410
Cdd:cd23129     5 CVVCMDAPRDAVCVPCGHVaGCMSCLKALMQSSP-LCPICRAPVRQV 50

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  463 ERPPSPFSVAPqAALP------PVPPRL--------DLLQQRVANP----PGASSPGTTSKAVPGALHKDKPL--PIPPT 522
Cdd:PHA03247  2507 DAPPAPSRLAP-AILPdepvgePVHPRMltwirgleELASDDAGDPppplPPAAPPAAPDRSVPPPRPAPRPSepAVTSR 2585

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  523 LRDLPPPPPPDRPHSIGAEGRPQRRPLPCT--PGDCPSRDKPPPVPSNRQAELWPSRPMPkAPSVALSPGDPWAGRELSN 600
Cdd:PHA03247  2586 ARRPDAPPQSARPRAPVDDRGDPRGPAPPSplPPDTHAPDPPPPSPSPAANEPDPHPPPT-VPPPERPRDDPAPGRVSRP 2664

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  601 RHSLPFSLPSQMDS-------RAESHRLGSTVSL----DNPVSLNTGPPTTSECEHPKIKPSSSANAIYSLAARPLP--- 666
Cdd:PHA03247  2665 RRARRLGRAAQASSppqrprrRAARPTVGSLTSLadppPPPPTPEPAPHALVSATPLPPGPAAARQASPALPAAPAPpav 2744

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  667 --VPKLPPGEQSESDEDTEYMSPSS----LPVVPPGPAVQKPELKMPLEMTQSLRVSECEQQTEACMYEAMYNIHSQAAS 740
Cdd:PHA03247  2745 paGPATPGGPARPARPPTTAGPPAPappaAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASP 2824

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  741 SAFEAVSTSDAGdlAAASASNGPEESENEEDGYDVP----------KPPLPVATARRTLSDISNATPAFSRmslendPVT 810
Cdd:PHA03247  2825 AGPLPPPTSAQP--TAPPPPPGPPPPSLPLGGSVAPggdvrrrppsRSPAAKPAAPARPPVRRLARPAVSR------STE 2896

                          410
                   ....*....|....*..
gi 2456637085  811 GFSDGSQVPERPPKPLP 827
Cdd:PHA03247  2897 SFALPPDQPERPPQPQA 2913

RING finger, HC subclass, found in RING finger protein 5 (RNF5) and similar proteins; RNF5, also known as protein G16 or Ram1, is an E3 ubiquitin-protein ligase anchored to the outer membrane of the endoplasmic reticulum (ER). It 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. It also regulates the turnover of specific G protein-coupled receptors by ubiquitinating JNK-associated membrane protein (JAMP) and preventing proteasome recruitment. RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection through the regulation of ATG4B stability. It is also involved in the degradation of Pendrin, a transmembrane chloride/anion exchanger highly expressed in thyroid, kidney, and inner ear. RNF5 plays an important role in cell adhesion and migration. It can modulate cell migration by ubiquitinating paxillin. Furthermore, RNF5 interacts with virus-induced signaling adaptor (VISA) at mitochondria in a viral infection-dependent manner, and further targets VISA at K362 and K461 for K48-linked ubiquitination and degradation after viral infection. It also negatively regulates virus-triggered signaling by targeting MITA, also known as STING, for ubiquitination and degradation at the mitochondria. In addition, RNF5 determines breast cancer response to ER stress-inducing chemotherapies through the regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2). It also has been implicated in muscle organization and in recognition and processing of misfolded proteins. RNF5 contains a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2456637085 365 CKICAENDKDVKIEPCGHLMCTSCLTAWQES--EGQGCPFCRCEI 407
Cdd:cd16743     3 CNICLETARDAVVSLCGHLFCWPCLHQWLETrpERQECPVCKAGI 47

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        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2456637085 364 LCKICAENDKD-VKIEPCGHLMCTSCLTAWQESEGQGCPFCRCEIKGTEP 412
Cdd:cd16544     4 TCPVCQEVLKDpVELPPCRHIFCKACILLALRSSGARCPLCRGPVGKTER 53

RING finger, HC subclass, found in RING finger protein 213 (RNF213) and similar proteins; RNF213, also known as ALK lymphoma oligomerization partner on chromosome 17 or Moyamoya steno-occlusive disease-associated AAA+ and RING finger protein (mysterin), is an intracellular soluble protein that functions as an E3 ubiquitin-protein ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell. It plays a unique role in endothelial cells for proper gene expression in response to inflammatory signals from the environment. Mutations in RNF213 may be associated with Moyamoya disease (MMD), an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. It also acts as a nuclear marker for acanthomorph phylogeny. RNF213 contains two tandem enzymatically active AAA+ ATPase modules and a C3HC4-type RING-HC finger. It can form a huge ring-shaped oligomeric complex.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 2456637085 363 QLCKICAENDKDVKIEPCGHLMCTSCLTAWQESEGQgCPFCRCEIK 408
Cdd:cd16561     3 QECSICLEDLNDPVKLPCDHVFCEECIRQWLPGQMS-CPLCRTELP 47

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 2456637085 365 CKICAENDKDVKIEPCGHLMCTSCLTAWQE--SEGQGCPFCR 404
Cdd:cd16534     3 CNICLDTASDPVVTMCGHLFCWPCLYQWLEtrPDRQTCPVCK 44

RING finger, HC subclass, found in RING finger protein 141 (RNF141) and similar proteins; RNF141, also known as zinc finger protein 230 (ZNF230), is a RING finger protein present primarily in the nuclei of spermatogonia, the acrosome, and the tail of spermatozoa. It may have a broad function during early development of vertebrates. It plays an important role in spermatogenesis, including spermatogenic cell proliferation and sperm maturation, as well as motility and fertilization. It also exhibits DNA binding activity. RNF141/ZNF230 gene mutations may be associated with azoospermia. RNF141 contains a C3HC4-type RING finger domain that may function as an activator module in transcription.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2456637085 365 CKICAENDKDVkIEPCGHLMCTSCLTAWQESEGQgCPFCR 404
Cdd:cd16545     3 CCICMDRKADL-ILPCAHSYCQKCIDKWSDRHRT-CPICR 40

RING finger, HC subclass, found in apoptosis protein c-IAP1, c-IAP2, livin, and similar proteins; The cellular inhibitor of apoptosis protein c-IAPs function as ubiquitin E3 ligases that mediate the ubiquitination of substrates involved in apoptosis, nuclear factor-kappaB (NF-kappaB) signaling, and oncogenesis. Unlike other IAPs, such as XIAP, c-IAPs exhibit minimal binding to caspases and may not play an important role in the inhibition of these proteases. c-IAP1, also known as baculoviral IAP repeat-containing protein BIRC2, IAP-2, RING finger protein 48, or TNFR2-TRAF-signaling complex protein 2, is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. It can also regulate E2F1 transcription factor-mediated control of cyclin transcription in the nucleus. c-IAP2, also known as BIRC3, IAP-1, apoptosis inhibitor 2 (API2), or IAP homolog C, also influences ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-kappaB. c-IAPs 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), a caspase activation and recruitment domain (CARD) that serves as a protein interaction surface, and a C3HC4-type RING-HC finger at the carboxyl terminus that is required for ubiquitin ligase activity. Livin, also known as baculoviral IAP repeat-containing protein 7 (BIRC7), kidney inhibitor of apoptosis protein (KIAP), melanoma inhibitor of apoptosis protein (ML-IAP), or RING finger protein 50, was identified as the melanoma IAP. It plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is regulated by the inhibition of caspase-3, -7, and -9. Its E3 ubiquitin-ligase-like activity promotes degradation of Smac/DIABLO, a critical endogenous regulator of all IAPs. Unlike other family members, mammalian livin contains a single BIR domain and a C3HC4-type RING-HC finger. The UBA domain can be detected in non-mammalian homologs of livin.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2456637085 365 CKICAENDKDVKIEPCGHLM-CTSCLTAWQEsegqgCPFCRCEIKGT 410
Cdd:cd16713    10 CKVCMDKEVSIVFIPCGHLVvCTECAPSLRK-----CPICRATIKGT 51

UBA/TS-N domain; This small domain is composed of three alpha helices. This family includes the previously defined UBA and TS-N domains. The UBA-domain (ubiquitin associated domain) is a novel sequence motif found in several proteins having connections to ubiquitin and the ubiquitination pathway. The structure of the UBA domain consists of a compact three helix bundle. This domain is found at the N terminus of EF-TS hence the name TS-N. The structure of EF-TS is known and this domain is implicated in its interaction with EF-TU. The domain has been found in non EF-TS proteins such as alpha-NAC and MJ0280.

                          10        20        30
                  ....*....|....*....|....*....|....*
gi 2456637085 855 SSEIENLLSQGYSYQDIQKALLIAHNNIEMAKNIL 889
Cdd:pfam00627   3 EEAIQRLVEMGFDREQVREALRATGNNVERAAEYL 37

transcriptional regulator ICP4; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  450 SLFMMKELAGTKVERPPSPFSVAPQAALPPVPPRLDLLQQRVANPPGASSPGTTSKAVPGalhkDKPLPIPPTLRDLPPP 529
Cdd:PHA03307     9 DLIEAAAEGGEFFPRPPATPGDAADDLLSGSQGQLVSDSAELAAVTVVAGAAACDRFEPP----TGPPPGPGTEAPANES 84

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  530 PPPDRPHSIGAEGRPQRRPLPCTPGDCPSRDKPPPVPSnrqaelwPSRPMPKAPSvALSPGDPWAGRELSNRH--SLPFS 607
Cdd:PHA03307    85 RSTPTWSLSTLAPASPAREGSPTPPGPSSPDPPPPTPP-------PASPPPSPAP-DLSEMLRPVGSPGPPPAasPPAAG 156

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  608 LPSQMDSRAESHRLGSTVSLDNPVSLNTGPPTTSECEHPKI-----KPSSSANAIYSLAARPLPVPKLPPGEQSESDEDT 682
Cdd:PHA03307   157 ASPAAVASDAASSRQAALPLSSPEETARAPSSPPAEPPPSTppaaaSPRPPRRSSPISASASSPAPAPGRSAADDAGASS 236

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  683 EYMSPSSLPVVPPGPavqkpELKMPLEMTQSLRVSECEQQteacmyeamyniHSQAASSAFEAVSTSDAGdlaAASASNG 762
Cdd:PHA03307   237 SDSSSSESSGCGWGP-----ENECPLPRPAPITLPTRIWE------------ASGWNGPSSRPGPASSSS---SPRERSP 296

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  763 PEESENEEDGYDVPKPPL--------PVATARRTLSDISNATPAFSRMSLENDPVtgfSDGSQVPERPPKPLPRRINSER 834
Cdd:PHA03307   297 SPSPSSPGSGPAPSSPRAsssssssrESSSSSTSSSSESSRGAAVSPGPSPSRSP---SPSRPPPPADPSSPRKRPRPSR 373

                          410
                   ....*....|..
gi 2456637085  835 KAGSCPPGGASS 846
Cdd:PHA03307   374 APSSPAASAGRP 385

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 2456637085 364 LCKICAENDKDVKIEPCGHLMCTSCLTAWQESEgQGCPFCR 404
Cdd:cd16532     2 ICPICQDEFKDPVVLRCKHIFCEDCVSEWFERE-RTCPLCR 41

RING finger, H2 subclass, found in synoviolin and similar proteins; Synoviolin, also known as synovial apoptosis inhibitor 1 (Syvn1), Hrd1, or Der3, is an endoplasmic reticulum (ER)-anchoring E3 ubiquitin ligase that functions as a suppressor of ER stress-induced apoptosis and plays a role in homeostasis maintenance. It also targets tumor suppressor gene p53 for proteasomal degradation, suggesting crosstalk between ER associated degradation (ERAD) and p53 mediated apoptotic pathway under ER stress. Moreover, synoviolin controls body weight and mitochondrial biogenesis through negative regulation of the thermogenic coactivator peroxisome proliferator-activated receptor coactivator (PGC)-1beta. It upregulates amyloid beta production by targeting a negative regulator of gamma-secretase, Retention in endoplasmic reticulum 1 (Rer1), for degradation. It is also involved in the degradation of endogenous immature nicastrin, and affects amyloid beta-protein generation. Moreover, synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of rheumatoid arthritis (RA). It functions as an anti-apoptotic factor that is responsible for the outgrowth of synovial cells during the development of RA. It promotes inositol-requiring enzyme 1 (IRE1) ubiquitination and degradation in synovial fibroblasts with collagen-induced arthritis. Furthermore, the upregulation of synoviolin may represent a protective response against neurodegeneration in Parkinson's disease (PD). In addition, synoviolin is involved in liver fibrogenesis. Synoviolin contains a C3H2C2-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2456637085 363 QLCKICAEN-DKDVKIEPCGHLMCTSCLTAWQESEgQGCPFCR 404
Cdd:cd16479     2 NTCIICREEmTVGAKKLPCGHIFHLSCLRSWLQRQ-QTCPTCR 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 2456637085 365 CKICAEN---DKDVKIEPCGHLMCTSCLTAWQESEGQgCPFCRC 405
Cdd:cd16465     2 CPICCSEyvkDEIATELPCHHLFHKPCITAWLQKSGT-CPVCRH 44

RING finger, H2 subclass, found in autocrine motility factor receptor (AMFR) and similar proteins; AMFR, also known as AMF receptor, or RING finger protein 45, or ER-protein gp78, is an internalizing cell surface glycoprotein localized in both plasma membrane caveolae and the endoplasmic reticulum (ER). It is involved in the regulation of cellular adhesion, proliferation, motility and apoptosis, as well as in the process of learning and memory. AMFR also functions as a RING finger-dependent ubiquitin protein ligase (E3) implicated in the degradation from the ER. AMFR contains an N-terminal RING-H2 finger and a C-terminal ubiquitin-associated (UBA)-like CUE domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2456637085 365 CKICAENDKDVKIEPCGHLMCTSCLTAWQEsEGQGCPFCR 404
Cdd:cd16455     3 CAICWESMQSARKLPCGHLFHNSCLRSWLE-QDTSCPTCR 41

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2456637085 365 CKICAENDKDVKIEPCGHLMCTSCLTAW--QESEGQGCPFCRCEIKG 409
Cdd:cd16611     7 CPLCLDFFRDPVMLSCGHNFCQSCITGFweLQAEDTTCPECRELCQY 53

RING finger, HC subclass, found in tripartite motif-containing protein 62 (TRIM62) and similar proteins; TRIM62, also known as Ductal Epithelium Associated Ring Chromosome 1 (DEAR1), is a cytoplasmic E3 ubiquitin-protein ligase that was identified as a dominant regulator of acinar morphogenesis in the mammary gland. It is implicated in the inflammatory response of immune cells by regulating the Toll-like receptor 4 (TLR4) signaling pathway, leading to increased activity of the activator protein 1 (AP-1) transcription factor in primary macrophages. It is also involved in muscular protein homeostasis, especially during inflammation-induced atrophy, and may play a role in the pathogenesis of ICU-acquired weakness (ICUAW) by activating and maintaining inflammation in myocytes. Moreover, TRIM62 facilitates K27-linked poly-ubiquitination of CARD9 and also regulates CARD9-mediated anti-fungal immunity and intestinal inflammation. It also functions as a chromosome 1p35 tumor suppressor and negatively regulates transforming growth factor beta (TGFbeta)-driven epithelial-mesenchymal transition (EMT) by binding to and promoting the ubiquitination of SMAD3, a major effector of TGFbeta-mediated EMT. TRIM62 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 2456637085 364 LCKICAENDKDVKIEPCGHLMCTSCLTA-WQESEGQGCPFCR 404
Cdd:cd16608     8 LCSICLSIYQDPVSLGCEHYFCRQCITEhWSRSEHRDCPECR 49

transcriptional regulator ICP4; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  465 PPSPFSVAPQAALPPVPPrLDLLQQRVANPPGASSPGTTSK----AVPGALHKDKPLPIPPTLRDLPPPPPPDRPHSIGA 540
Cdd:PHA03307    72 PPGPGTEAPANESRSTPT-WSLSTLAPASPAREGSPTPPGPsspdPPPPTPPPASPPPSPAPDLSEMLRPVGSPGPPPAA 150

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  541 EGRPQRRPLPCTPGDCPS-RDKPPPVPSNRQAELWPSRPM----PKAPSVALSPGDPWAGRELSNRHSLPFSLPSQMDsr 615
Cdd:PHA03307   151 SPPAAGASPAAVASDAASsRQAALPLSSPEETARAPSSPPaeppPSTPPAAASPRPPRRSSPISASASSPAPAPGRSA-- 228

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  616 aESHRLGSTVSLDNPVSLNTGPPTTSEC----EHPKIKPSSSANAIYSLAARPLPVPKLPPGEQSESDEDTEYMSPSSLP 691
Cdd:PHA03307   229 -ADDAGASSSDSSSSESSGCGWGPENECplprPAPITLPTRIWEASGWNGPSSRPGPASSSSSPRERSPSPSPSSPGSGP 307

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2456637085  692 VVPPGPAVQKPELKMPLEMTQSLRVSECEQQTEAcmyeamynihSQAASSAFEAVSTSDAGDLAAASASNGPEESeneed 771
Cdd:PHA03307   308 APSSPRASSSSSSSRESSSSSTSSSSESSRGAAV----------SPGPSPSRSPSPSRPPPPADPSSPRKRPRPS----- 372

                          330       340       350       360       370       380       390
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2456637085  772 gydvPKPPLPVATARRtlSDISNATPAFSRMSLENDpvTGFSDGSQVPerPPKPLPRRINSERKAGSCPPGGAS 845
Cdd:PHA03307   373 ----RAPSSPAASAGR--PTRRRARAAVAGRARRRD--ATGRFPAGRP--RPSPLDAGAASGAFYARYPLLTPS 436

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 2456637085 365 CKICAENDKDVKIEPCGHLMCTSCLTAWQESEGQGCPFCRCEIK 408
Cdd:cd16509     6 CAICLDSLTNPVITPCAHVFCRRCICEVIQREKAKCPMCRAPLS 49