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 2789714000 241 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 320
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 2789714000 321 FYLYPDGRNQNPDLTGL 337
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 2789714000 343 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 419
Cdd:cd16708     1 QDHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 77

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2789714000  466 PPSPFSVAPQASLPPVPPRLDL---------------LQQRVSNPPGASSPGTTSKAAPGSLHKDKPLPIPPTHRDLPPP 530
Cdd:PHA03247  2831 PTSAQPTAPPPPPGPPPPSLPLggsvapggdvrrrppSRSPAAKPAAPARPPVRRLARPAVSRSTESFALPPDQPERPPQ 2910

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2789714000  531 PPPDRPHPVGADNRPQRRPLPCTPGDKLPPVPCnrqaelwPVRPIPKAPGSVALSSGEPWAGRDVTNRHSLP-FSLPSQM 609
Cdd:PHA03247  2911 PQAPPPPQPQPQPPPPPQPQPPPPPPPRPQPPL-------APTTDPAGAGEPSGAVPQPWLGALVPGRVAVPrFRVPQPA 2983

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2789714000  610 DSRAEP-------HRH--------GSTLSLDTTASNQPTGLPAGL----DAEHSKIKPSSSANAIYSLAARPLPGPKLPH 670
Cdd:PHA03247  2984 PSREAPasstpplTGHslsrvsswASSLALHEETDPPPVSLKQTLwppdDTEDSDADSLFDSDSERSDLEALDPLPPEPH 3063

                          250       260       270
                   ....*....|....*....|....*....|.
gi 2789714000  671 GEPS-END----EDTEYMSPSSLPLVPPLAS 696
Cdd:PHA03247  3064 DPFAhEPDpatpEAGARESPSSQFGPPPLSA 3094

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 2789714000 241 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 320
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 2789714000 321 FYLYPDGRNQNPDLTGL 337
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 2789714000 164 FRITKADAAEFWRKAFGEKTIVPWKIFRPALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNW 243
Cdd:pfam02761   1 FRITKSEAAEFWKKSFGKRTIVPWKEFRTALQQVHGIESGLEAMALKSTIDLTCNDHISIFEFDVFTRLFQPWSTLLRNW 80

                  ....
gi 2789714000 244 NSLA 247
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 2789714000 856 LSSEIESLMSQGYSYQDIQKALVIAHNNIDMAKNILREFV 895
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 2789714000  366 CKICAEN-DKDVKIEPCGHLMCTSCLTSWQESEGQGCPFC 404
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 2789714000  856 LSSEIESLMSQGYSYQDIQKALVIAHNNIDMAKNIL 891
Cdd:smart00165   1 DEEKIDQLLEMGFSREEALKALRAANGNVERAAEYL 36

RING-finger-containing E3 ubiquitin ligase [Posttranslational modification, protein turnover, chaperones];

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCL-TSWQESEGQGCPFCR 405
Cdd:COG5574   218 CFLCLEEPEVPSCTPCGHLFCLSCLlISWTKKKYEFCPLCR 258

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 2789714000 241 RNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRLGQWAIGYVTADGNILQTIPHNKPLFQALIDGFREG 320
Cdd:cd09920     1 RNWQVLAVTHPGYMAFLTYDEVKARLQKFRDKPGSYVFRLSCTRLGQWAIGYVTADGKILQTIPQNKSLCQALIDGSREG 80

                          90
                  ....*....|....*..
gi 2789714000 321 FYLYPDGRNQNPDLTGL 337
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 2789714000 164 FRITKADAAEFWRKAFGEKTIVPWKIFRPALHEVHPISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLFQPWSSLLRNW 243
Cdd:pfam02761   1 FRITKSEAAEFWKKSFGKRTIVPWKEFRTALQQVHGIESGLEAMALKSTIDLTCNDHISIFEFDVFTRLFQPWSTLLRNW 80

                  ....
gi 2789714000 244 NSLA 247
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 2789714000 344 DHIKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCRCEIKGTEPIVVDPF 419
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 2789714000 363 FQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCR 405
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 2789714000 856 LSSEIESLMSQGYSYQDIQKALVIAHNNIDMAKNILREFV 895
Cdd:cd14318     1 LLSYIAKLVGEGYSKEDVIRALGIARNNVEMARDILREFA 40

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 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCLTSWQESegqGCPFCRCEIKGTEPI 414
Cdd:pfam14447   1 CVLCGRNGTVHALIPCGHLVCRDCFDGSDFS---ACPICRRRIDADDPF 46

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 2789714000  366 CKICAEN-DKDVKIEPCGHLMCTSCLTSWQESEGQGCPFC 404
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 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFC 404
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 2789714000 364 QLCKICAENDKDVKIEPCGHL-MCTSCLtswQESEGQGCPFCR 405
Cdd:cd16649     1 GLCVVCLENPASVLLLPCRHLcLCEVCA---KGLRGKTCPICR 40

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        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCLTSWQESE--GQGCPFCRCEIKGTEPI 414
Cdd:cd16744     3 CNICLDTAKDAVVSLCGHLFCWPCLHQWLETRpnRQVCPVCKAGISRDKVI 53

Modified RING finger, HC subclass (C3HC5-type), found in neuralized-like protein NEURL1A, NEURL1B, and similar proteins; This subfamily includes Drosophila neuralized (D-neu) protein, and its two mammalian homologs, NEURL1A and NEURL1B. D-neu is a regulator of the developmentally important Notch signaling pathway. NEURL1A, also known as NEURL1, NEU, neuralized 1, or RING finger protein 67 (RNF67), is a mammalian homolog of D-neu. 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 medulloblastoma. NEURL1B, also known as neuralized-2 (NEUR2) or neuralized-like protein 3, is another mammalian homolog of D-neu protein. It functions as an E3 ubiquitin-protein ligase that interacts with and ubiquitinates Delta. Thus, it plays a role in the endocytic pathways for Notch signaling by working cooperatively with another E3 ligase, Mind bomb-1 (Mib1), in Delta endocytosis to hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-positive vesicles. Members of this subfamily contain 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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2789714000 366 CKICAENDKDVKIEPCGHL-MCTSCLTSWQESEGQgCPFCRCEIK 409
Cdd:cd16647     4 CVICYERPVDTVLYRCGHMcMCYDCALQLKRRGGS-CPICRAPIK 47

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 2789714000 364 QLCKICAENDKDVKIEPCGHLM-CTSCLTSWQEsegqgCPFCR 405
Cdd:cd16510     2 KLCKICMDREVNIVFLPCGHLVtCAQCAASLRK-----CPICR 39

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2789714000  466 PPSPFSVAPQASLPPVPPRLDL---------------LQQRVSNPPGASSPGTTSKAAPGSLHKDKPLPIPPTHRDLPPP 530
Cdd:PHA03247  2831 PTSAQPTAPPPPPGPPPPSLPLggsvapggdvrrrppSRSPAAKPAAPARPPVRRLARPAVSRSTESFALPPDQPERPPQ 2910

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2789714000  531 PPPDRPHPVGADNRPQRRPLPCTPGDKLPPVPCnrqaelwPVRPIPKAPGSVALSSGEPWAGRDVTNRHSLP-FSLPSQM 609
Cdd:PHA03247  2911 PQAPPPPQPQPQPPPPPQPQPPPPPPPRPQPPL-------APTTDPAGAGEPSGAVPQPWLGALVPGRVAVPrFRVPQPA 2983

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2789714000  610 DSRAEP-------HRH--------GSTLSLDTTASNQPTGLPAGL----DAEHSKIKPSSSANAIYSLAARPLPGPKLPH 670
Cdd:PHA03247  2984 PSREAPasstpplTGHslsrvsswASSLALHEETDPPPVSLKQTLwppdDTEDSDADSLFDSDSERSDLEALDPLPPEPH 3063

                          250       260       270
                   ....*....|....*....|....*....|.
gi 2789714000  671 GEPS-END----EDTEYMSPSSLPLVPPLAS 696
Cdd:PHA03247  3064 DPFAhEPDpatpEAGARESPSSQFGPPPLSA 3094

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 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCLTSWQE--SEGQGCPFCR 405
Cdd:cd16534     3 CNICLDTASDPVVTMCGHLFCWPCLYQWLEtrPDRQTCPVCK 44

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 2789714000 366 CKICAENDKDVKIEPCGHLM-CTSCLTSWQEsegqgCPFCRCEIKGT 411
Cdd:cd16713    10 CKVCMDKEVSIVFIPCGHLVvCTECAPSLRK-----CPICRATIKGT 51

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 2789714000 364 QLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQgCPFCRCEIK 409
Cdd:cd16561     3 QECSICLEDLNDPVKLPCDHVFCEECIRQWLPGQMS-CPLCRTELP 47

RING finger, H2 subclass, found in TRAF-interacting protein (TRAIP) and similar proteins; TRAIP, also known as RING finger protein 206 (RNF206) or TRIP, is a ubiquitously expressed nucleolar E3 ubiquitin ligase important for cellular proliferation and differentiation. It is found near mitotic chromosomes and functions as a regulator of the spindle assembly checkpoint. TRAIP interacts with tumor necrosis factor (TNF)-receptor-associated factor (TRAF) proteins and inhibits TNF-alpha-mediated nuclear factor (NF)-kappaB activation. It also interacts with two tumor suppressors CYLD and spleen tyrosine kinase (Syk), and DNA polymerase eta, which facilitates translesional synthesis after DNA damage. TRAIP contains an N-terminal C3H2C2-type RING-H2 finger and an extended coiled-coil domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 2789714000 365 LCKICAE---NDKDVKIEPCGHLMCTSCLTSWQESEgQGCPFCR 405
Cdd:cd16480     1 YCTICSDffdNSRDVAAIHCGHTFHYDCLLQWFDTS-RTCPQCR 43

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 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCLTSWQEsEGQGCPFCR 405
Cdd:cd16455     3 CAICWESMQSARKLPCGHLFHNSCLRSWLE-QDTSCPTCR 41

RING finger, HC subclass, found in caspases-8 and -10-associated RING finger protein CARP-1, CARP-2 and similar proteins; The CARP subfamily includes CARP-1 and CARP-2 proteins, both of which are E3 ubiquitin ligases that ubiquitinate apical caspases and target them for proteasome-mediated degradation. As a novel group of caspase regulators with a FYVE-type zinc finger domain, they do not localize to membranes in the cell and are involved in the negative regulation of apoptosis, specifically targeting two initiator caspases, caspase 8, and caspase 10. Moreover, they stabilize MDM2 by inhibiting MDM2 self-ubiquitination, as well as by targeting 14-3-3sigma for degradation. They work together with MDM2 to enhance p53 degradation, thereby inhibiting p53-mediated cell death. CARPs contain an N-terminal FYVE-like domain that can serve as a membrane-targeting or endosome localizing signal and a C-terminal C3HC4-type RING-HC finger domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 2789714000 365 LCKICAENDKDVKIEPCGHLM-CTSCltSWQESEgqgCPFCR 405
Cdd:cd16500     2 LCKICMDAAIDCVLLECGHMVtCTDC--GKKLSE---CPICR 38

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 2789714000 365 LCKICAENDKDVKIEPCGHLMCTSCLTSWQESEgQGCPFCR 405
Cdd:cd16532     2 ICPICQDEFKDPVVLRCKHIFCEDCVSEWFERE-RTCPLCR 41

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.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 2789714000 360 GSTFQLCKICAENDKDVKIEPCGHL-MCTSCLTSWQESEGQGCPFCRCEIK 409
Cdd:cd16785     1 GSWSDECTICYENAVDTVIYTCGHMcLCYACGLRLKKMLNACCPICRRAIK 51

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.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCLTS---WQESEGQGCPFCRCE 407
Cdd:cd16597     8 CSICLELFKDPVTLPCGHNFCGVCIEKtwdSQHGSEYSCPQCRAT 52

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 2789714000 365 LCKICAENDKDVKIEPCGHLMCTSCLTS-WQESEGQGCPFCR 405
Cdd:cd16608     8 LCSICLSIYQDPVSLGCEHYFCRQCITEhWSRSEHRDCPECR 49

RING finger, HC subclass, found in tripartite motif-containing protein 39 (TRIM39) and similar proteins; TRIM39, also known as RING finger protein 23 (RNF23) or testis-abundant finger protein, is an E3 ubiquitin-protein ligase that plays a role in controlling DNA damage-induced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others. TRIM39 also functions as a regulator of several key processes in the proliferative cycle. It directly regulates p53 stability. It modulates cell cycle progression and DNA damage responses via stabilizing p21. Moreover, TRIM39 negatively regulates the nuclear factor kappaB (NFkappaB)-mediated signaling pathway through stabilization of Cactin, an inhibitor of NFkappaB- and Toll-like receptor (TLR)-mediated transcription, which is induced by inflammatory stimulants such as tumor necrosis factor alpha. Furthermore, TRIM39 is a MOAP-1-binding protein that can promote apoptosis signaling through stabilization of MOAP-1 via the inhibition of its poly-ubiquitination process. TRIM39 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 2789714000 365 LCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQG--CPFC 404
Cdd:cd16601     3 SCSLCKEYLKDPVIIECGHNFCRACITRFWEELDGDfpCPQC 44

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 2789714000 366 CKICAENDKDVKIEPCGHLMCTSCL-TSWQESEGQG--CPFCRCE 407
Cdd:cd16609     6 CSICLGLYQDPVTLPCQHSFCRACIeDHWRQKDEGSfsCPECRAP 50

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 2789714000 366 CKICAEN---DKDVKIEPCGHLMCTSCLTSWQESEGQgCPFCRC 406
Cdd:cd16465     2 CPICCSEyvkDEIATELPCHHLFHKPCITAWLQKSGT-CPVCRH 44

RING finger, HC subclass, found in Arabidopsis thaliana MND1-interacting protein 1 (MIP1) and similar proteins; This subfamily includes Arabidopsis thaliana MIP1, RING finger protein 4 (RF4) and RING finger protein 298 (RF298). MIP1 interacts with MND1, HOP2 and XRI1. RF4 and RF298 are putative E3 ubiquitin-protein ligase that may mediate E2-dependent protein ubiquitination. Members of this subfamily contain a typical C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 2789714000 366 CKICAENDKDVKIEPCGHL-MCTSCLTSWQESEGQGCPFCRCEIK 409
Cdd:cd23128     6 CVMCMEEERSVVFLPCAHQvVCSGCNDLHEKKGMRECPSCRGEIQ 50

RING finger, H2 subclass, found in RING finger protein 165 (RNF165) and similar proteins; RNF165, also known as Arkadia-like 2, Arkadia2, or Ark2C, is an E3 ubiquitin ligase with homology to the C-terminal half of RNF111. It is expressed specifically in the nervous system, and can serve to amplify neuronal responses to specific signals. It acts as a positive regulator of bone morphogenetic protein (BMP)-Smad signaling that is involved in motor neuron (MN) axon elongation. RNF165 contains two serine rich domains, a nuclear localization signal, an NRG-TIER domain, and a C-terminal C3H2C3-type RING-H2 finger that is responsible for the enhancement of BMP-Smad1/5/8 signaling in the spinal cord.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2789714000 358 EMGSTFQLCKICA---ENDKDVKIEPCGHLMCTSCLTSWQeSEGQGCPFCRCEIK 409
Cdd:cd16682     2 EESDTDEKCTICLsmlEDGEDVRRLPCMHLFHQLCVDQWL-AMSKKCPICRVDIE 55

zinc-RING finger domain;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 2789714000 366 CKICAE---NDKDVKIEPCGHLMCTSCLTswQESEGQGCPFCR 405
Cdd:pfam14634   2 CNKCFKelsKTRPFYLTSCGHIFCEECLT--RLLQERQCPICK 42

RING finger, HC subclass, found in RING finger and SPRY domain-containing protein 1 (RSPRY1) and similar proteins; RSPRY1 is a hypothetical RING and SPRY domain-containing protein of unknown physiological function. Mutations in its corresponding gene RSPRY1 may associate with a distinct skeletal dysplasia syndrome. RSPRY1 contains a B30.2/SPRY domain and a C3HC4-type RING-HC finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 2789714000 366 CKICAENDKDVKIEPCGH----LMCTSCLTSwqesegqgCPFCRCEI 408
Cdd:cd16566     5 CTLCFDKVADTELRPCGHsgfcMECALQLET--------CPLCRQPI 43

RING finger, HC subclass, found in Arabidopsis thaliana protein XB3 homolog 1 (XBAT31) and similar proteins; XBAT31, also called ankyrin repeat domain and RING finger-containing protein XBAT31, or RING-type E3 ubiquitin transferase XB31, has no E3 ubiquitin-protein ligase activity observed when associated with the E2 enzyme UBC8 in vitro. XBAT31 contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2789714000 361 STFQLCKICAENDKDVKIEPCGHLMCTSCL----------TSWQESEGQGCPFCRCEI 408
Cdd:cd23144     4 SDEDVCCICFEHLCTIEIKDCGHQMCATCAlklcchnkpnPSSSPPRPPACPFCRQDI 61

H2 subclass of RING (RING-H2) fingers 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 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). This family corresponds to the H2 subclass of RING (RING-H2) finger proteins that are characterized by containing C3H2C3-type canonical RING-H2 fingers or noncanonical RING-H2 finger variants, including C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type modified RING-H2 fingers. The canonical RING-H2 finger has been defined as C-X2-C-X(9-39)-C-X(1-3)-H-X(2-3)-H-X2-C-X(4-48)-C-X2-C, X is any amino acid and the number of X residues varies in different fingers. It binds two Zn ions in a unique "cross-brace" arrangement, which distinguishes it from tandem zinc fingers and other similar motifs. RING-H2 finger 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 serves as a scaffold 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        40
                  ....*....|....*....|....*....|....*....|...
gi 2789714000 366 CKICAENDKD---VKIEPCGHLMCTSCLTSWQESEGQGCPFCR 405
Cdd:cd16448     1 CVICLEEFEEgdvVRLLPCGHVFHLACILRWLESGNNTCPLCR 43

RING finger, HC subclass, found in tripartite motif-containing protein 2 (TRIM2); TRIM2, also known as RING finger protein 86 (RNF86), is an E3 ubiquitin-protein ligase that ubiquitinates the neurofilament light chain, a component of the intermediate filament in axons. Loss of function of TRIM2 results in early-onset axonal neuropathy. TRIM2 also plays a role in mediating the p42/p44 MAPK-dependent ubiquitination of the cell death-promoting protein Bcl-2-interacting mediator of cell death (Bim) in rapid ischemic tolerance. TRIM2 belongs to the C-VII subclass of the TRIM (tripartite motif)-NHL family that is 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 domain, as well as a NHL (named after proteins NCL-1, HT2A and Lin-41 that contain repeats folded into a six-bladed beta propeller) repeat domain positioned C-terminal to the RBCC domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 2789714000 358 EMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSW--QESEGQGCPFCR 405
Cdd:cd16767     1 QIDKQFLICSICLDRYKNPKVLPCLHTFCERCLQNYipAHSLTLSCPVCR 50

RING finger, HC subclass, found in Dictyostelium discoideum Ras guanine nucleotide exchange factor O (RasGEFO) and similar proteins; RasGEFO, also known as RasGEF domain-containing protein O, functions as a Ras guanine-nucleotide exchange factor (RasGEFs), activating Ras by catalyzing the replacement of GDP with GTP. RasGEFs are particularly important for signaling in development and chemotaxis in many organisms, including Dictyostelium. RasGEFO contains a C3HC4-type RING-HC finger that may be responsible for E3 ubiquitin ligase activity.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 2789714000 366 CKICAENDKDVK-IEPCGHLMCTSCLTSwqESEGQGCPFCRCEIKGTE 412
Cdd:cd16507    12 CGICQNLFKDPNtLIPCGHAFCLDCLTT--NASIKNCIQCKVEYTTYI 57