Tripartite motif containing protein 37 (TRIM37) family, MATH domain; TRIM37 is a peroxisomal protein and is a member of the tripartite motif (TRIM) protein subfamily, also known as the RING-B-box-coiled-coil (RBCC) subfamily of zinc-finger proteins. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction and hepatomegaly. TRIM37, similar to other TRIMs, contains a cysteine-rich, zinc-binding RING-finger domain followed by another cysteine-rich zinc-binding domain, the B-box, and a coiled-coil domain. TRIM37 is autoubiquitinated in a RING domain-dependent manner, indicating that it functions as an ubiquitin E3 ligase. In addition to the tripartite motif, TRIM37 also contains a MATH domain C-terminal to the coiled-coil domain. The MATH domain of TRIM37 has been shown to interact with the TRAF domain of six known TRAFs in vitro, however, it is unclear whether this is physiologically relevant. Eleven TRIM37 mutations have been associated with Mulibrey nanism so far. One mutation, Gly322Val, is located in the MATH domain and is the only mutation that does not affect the length of the protein. It results in the incorrect subcellular localization of TRIM37.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290 273 VPSYDSATFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHQSc 352
Cdd:cd03773     1 IPPYDSATFTLENFSTLRQSADPVYSDPLNVDGLCWRLKVYPDGNGEVRGNFLSVFLELCSGLGEASKYEYRVEMVHQA- 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1386876290 353 nDPTKNIIREFASDFEVGECWGYNRFFRLDLLANEGYLNRQNDTVILRFQVRSP 406
Cdd:cd03773    80 -NPTKNIKREFASDFEVGECWGYNRFFRLDLLINEGYLLPENDTLILRFSVRPP 132

B-box-type 2 zinc finger found in tripartite motif-containing protein 37 (TRIM37) and similar proteins; TRIM37, also known as Mulibrey nanism protein, is a peroxisomal E3 ubiquitin-protein ligase that is involved in the tumorigenesis of several cancer types, including pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), breast cancer, and sporadic fibrothecoma. It mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. Moreover, TRIM37 possesses anti-HIV-1 activity, and interferes with viral DNA synthesis. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction, and hepatomegaly. TRIM37 belongs to the C-VIII 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 RING finger, Bbox2, and a coiled coil region, as well as a MATH (meprin and TRAF-C homology) domain positioned C-terminal to the RBCC domain. Its MATH domain has been shown to interact with the TRAF (TNF-Receptor-Associated Factor) domain of six known TRAFs in vitro. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1386876290  93 DKCENHHEKLSVFCWTCKKCICHQCALWGGMHGGHTFKPL 132
Cdd:cd19779     1 DKCETHNEKLSVYCWTCKKCICHQCALWGGTHSGHTFKPL 40

Tripartite motif containing protein 37 (TRIM37) family, MATH domain; TRIM37 is a peroxisomal protein and is a member of the tripartite motif (TRIM) protein subfamily, also known as the RING-B-box-coiled-coil (RBCC) subfamily of zinc-finger proteins. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction and hepatomegaly. TRIM37, similar to other TRIMs, contains a cysteine-rich, zinc-binding RING-finger domain followed by another cysteine-rich zinc-binding domain, the B-box, and a coiled-coil domain. TRIM37 is autoubiquitinated in a RING domain-dependent manner, indicating that it functions as an ubiquitin E3 ligase. In addition to the tripartite motif, TRIM37 also contains a MATH domain C-terminal to the coiled-coil domain. The MATH domain of TRIM37 has been shown to interact with the TRAF domain of six known TRAFs in vitro, however, it is unclear whether this is physiologically relevant. Eleven TRIM37 mutations have been associated with Mulibrey nanism so far. One mutation, Gly322Val, is located in the MATH domain and is the only mutation that does not affect the length of the protein. It results in the incorrect subcellular localization of TRIM37.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290 273 VPSYDSATFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHQSc 352
Cdd:cd03773     1 IPPYDSATFTLENFSTLRQSADPVYSDPLNVDGLCWRLKVYPDGNGEVRGNFLSVFLELCSGLGEASKYEYRVEMVHQA- 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1386876290 353 nDPTKNIIREFASDFEVGECWGYNRFFRLDLLANEGYLNRQNDTVILRFQVRSP 406
Cdd:cd03773    80 -NPTKNIKREFASDFEVGECWGYNRFFRLDLLINEGYLLPENDTLILRFSVRPP 132

B-box-type 2 zinc finger found in tripartite motif-containing protein 37 (TRIM37) and similar proteins; TRIM37, also known as Mulibrey nanism protein, is a peroxisomal E3 ubiquitin-protein ligase that is involved in the tumorigenesis of several cancer types, including pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), breast cancer, and sporadic fibrothecoma. It mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. Moreover, TRIM37 possesses anti-HIV-1 activity, and interferes with viral DNA synthesis. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction, and hepatomegaly. TRIM37 belongs to the C-VIII 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 RING finger, Bbox2, and a coiled coil region, as well as a MATH (meprin and TRAF-C homology) domain positioned C-terminal to the RBCC domain. Its MATH domain has been shown to interact with the TRAF (TNF-Receptor-Associated Factor) domain of six known TRAFs in vitro. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1386876290  93 DKCENHHEKLSVFCWTCKKCICHQCALWGGMHGGHTFKPL 132
Cdd:cd19779     1 DKCETHNEKLSVYCWTCKKCICHQCALWGGTHSGHTFKPL 40

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290  284 ENFSTLRqRADPVYSPPLQVSGLCWRLKVYPDGNgvvrgyYLSVFLELSAGLPETSKY--EYRVEMVHQSCNDptKNIIR 361
Cdd:smart00061   7 KNVSRLE-EGESYFSPSEEHFNIPWRLKIYRKNG------FLSLYLHCEKEECDSRKWsiEAEFTLKLVSQNG--KSLSK 77

                           90
                   ....*....|....*...
gi 1386876290  362 EFASDFEVGECWGYNRFF 379
Cdd:smart00061  78 KDKHVFEKPSGWGFSKFI 95

B-Box-type zinc finger;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1386876290   91 EKDKCENHH-EKLSVFCWTCKKCICHQCALWggMHGGHTFKPL 132
Cdd:smart00336   2 RAPKCDSHGdEPAEFFCEECGALLCRTCDEA--EHRGHTVVLL 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 1386876290   15 CFICMEKLRDARLCPHCSKLCCFSCIRRWLTEQRAQCPHC 54
Cdd:smart00184   1 CPICLEEYLKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

N1R/p28-like protein; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1386876290  15 CFICMEKLRDAR-------LCPHCSKLCCFSCIRRWlTEQRAQCPHCRAP 57
Cdd:PHA02929  177 CAICMEKVYDKEiknmyfgILSNCNHVFCIECIDIW-KKEKNTCPVCRTP 225

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1386876290  13 FRCFICMEKLRDArLCPHCSKLCCFSCIRRWLTEQRAQ-CPHCRAPLQLRElVNC 66
Cdd:COG5574   216 YKCFLCLEEPEVP-SCTPCGHLFCLSCLLISWTKKKYEfCPLCRAKVYPKK-VII 268

Uncharacterized coiled-coil protein, contains DUF342 domain [Function unknown];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290 132 LAEIYEQhVTKVNEEVAKLRRRLMELISLVQEV--ERN---------VEAVRNAKDER------VREIRNAVEMMIARLD 194
Cdd:COG1340    10 LEELEEK-IEELREEIEELKEKRDELNEELKELaeKRDelnaqvkelREEAQELREKRdelnekVKELKEERDELNEKLN 88

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1386876290 195 tQLKNKLITLMGQKTSLTQETELLESLLQEVEH 227
Cdd:COG1340    89 -ELREELDELRKELAELNKAGGSIDKLRKEIER 120

Tripartite motif containing protein 37 (TRIM37) family, MATH domain; TRIM37 is a peroxisomal protein and is a member of the tripartite motif (TRIM) protein subfamily, also known as the RING-B-box-coiled-coil (RBCC) subfamily of zinc-finger proteins. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction and hepatomegaly. TRIM37, similar to other TRIMs, contains a cysteine-rich, zinc-binding RING-finger domain followed by another cysteine-rich zinc-binding domain, the B-box, and a coiled-coil domain. TRIM37 is autoubiquitinated in a RING domain-dependent manner, indicating that it functions as an ubiquitin E3 ligase. In addition to the tripartite motif, TRIM37 also contains a MATH domain C-terminal to the coiled-coil domain. The MATH domain of TRIM37 has been shown to interact with the TRAF domain of six known TRAFs in vitro, however, it is unclear whether this is physiologically relevant. Eleven TRIM37 mutations have been associated with Mulibrey nanism so far. One mutation, Gly322Val, is located in the MATH domain and is the only mutation that does not affect the length of the protein. It results in the incorrect subcellular localization of TRIM37.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290 273 VPSYDSATFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHQSc 352
Cdd:cd03773     1 IPPYDSATFTLENFSTLRQSADPVYSDPLNVDGLCWRLKVYPDGNGEVRGNFLSVFLELCSGLGEASKYEYRVEMVHQA- 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1386876290 353 nDPTKNIIREFASDFEVGECWGYNRFFRLDLLANEGYLNRQNDTVILRFQVRSP 406
Cdd:cd03773    80 -NPTKNIKREFASDFEVGECWGYNRFFRLDLLINEGYLLPENDTLILRFSVRPP 132

MATH (meprin and TRAF-C homology) domain; an independent folding unit with an eight-stranded beta-sandwich structure found in meprins, TRAFs and other proteins. Meprins comprise a class of extracellular metalloproteases which are anchored to the membrane and are capable of cleaving growth factors, extracellular matrix proteins, and biologically active peptides. TRAF molecules serve as adapter proteins that link cell surface receptors of the Tumor Necrosis Factor and 1nterleukin-1/Toll-like families to downstream kinase cascades, which results in the activation of transcription factors and the regulation of cell survival, proliferation and stress responses in the immune and inflammatory systems. Other members include the ubiquitin ligases, TRIM37 and SPOP, and the ubiquitin-specific proteases, HAUSP and Ubp21p. A large number of uncharacterized members mostly from lineage-specific expansions in C. elegans and rice contain MATH and BTB domains, similar to SPOP. The MATH domain has been shown to bind peptide/protein substrates in TRAFs and HAUSP. It is possible that the MATH domain in other members of this superfamily also interacts with various protein substrates. The TRAF domain may also be involved in the trimerization of TRAFs. Based on homology, it is postulated that the MATH domain in meprins may be involved in its tetramer assembly and that the MATH domain, in general, may take part in diverse modular arrangements defined by adjacent multimerization domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290 280 TFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGvVRGYYLSVFLELSAGLPETS----KYEYRVEMVHQscnDP 355
Cdd:cd00121     2 KHTWKIVNFSELEGESIYSPPFEVGGYKWRIRIYPNGDG-ESGDYLSLYLELDKGESDLEkwsvRAEFTLKLVNQ---NG 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1386876290 356 TKNIIREFASDF--EVGECWGYNRFFRLDLLANEGYLNrqNDTVILRFQVR 404
Cdd:cd00121    78 GKSLSKSFTHVFfsEKGSGWGFPKFISWDDLEDSYYLV--DDSLTIEVEVK 126

Modified RING finger, HC subclass (C4C4-type), found in tripartite motif-containing protein 37 (TRIM37) and similar proteins; TRIM37, also known as mulibrey nanism protein, or MUL, is a peroxisomal E3 ubiquitin-protein ligase that is involved in the tumorigenesis of several cancer types, including pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), breast cancer, and sporadic fibrothecoma. It mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. Moreover, TRIM37 possesses anti-HIV-1 activity, and interferes with viral DNA synthesis. Mutations in the human TRIM37 gene (also known as MUL) cause Mulibrey (muscle-liver-brain-eye) nanism, a rare growth disorder of prenatal onset characterized by dysmorphic features, pericardial constriction, and hepatomegaly. TRIM37 belongs to the C-VIII 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 C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a MATH (meprin and TRAF-C homology) domain positioned C-terminal to the RBCC domain. Its MATH domain has been shown to interact with the TRAF (TNF-Receptor-Associated Factor) domain of six known TRAFs in vitro.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1386876290  13 FRCFICMEKLRDARLCPHCSKLCCFSCIRRWLTEQRAQCPHCR 55
Cdd:cd16619     1 FRCFICMEKLRDPRLCPHCSKLFCKGCIRRWLSEQRSSCPHCR 43

B-box zinc finger;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1386876290  90 NEKDKCENHH-EKLSVFCWTCKKCICHQCALwgGMHGGHTFKPL 132
Cdd:pfam00643   1 SKERLCPEHEeEPLTLYCNDCQELLCEECSV--GEHRGHTVVPL 42

B-box-type 2 zinc finger (Bbox2); The B-box-type zinc finger is a short zinc binding domain of around 40 amino acid residues in length. It has been found in transcription factors, ribonucleoproteins and proto-oncoproteins, such as in TRIM (tripartite motif) proteins that consist of an N-terminal RING finger (originally called an A-box), followed by 1-2 B-box domains and a coiled-coil domain (also called RBCC for Ring, B-box, Coiled-Coil). The B-box-type zinc finger often presents in combination with other motifs, like RING zinc finger, NHL motif, coiled-coil or RFP domain in functionally unrelated proteins, most likely mediating protein-protein interaction. Based on different consensus sequence and the spacing of the 7-8 zinc-binding residues, B-box-type zinc fingers can be divided into two groups, type 1 (Bbox1: C6H2) and type 2 (Bbox2: CHC3H2). The family corresponds to type 2 B-box (Bbox2).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1386876290  94 KCENHHEK-LSVFCWTCKKCICHQCALWgGMHGGHTFKPL 132
Cdd:cd19756     1 LCPEHPEEpLKLFCETCQELVCVLCLLS-GEHRGHKVVPL 39

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1386876290  13 FRCFICMEKLRDARLCPhCSKLCCFSCIRRWLTEqRAQCPHCRAPLQLRELV 64
Cdd:cd16527     1 RKCSLCLEERRHPTATP-CGHLFCWSCITEWCNE-KPECPLCREPFQPQRLV 50

Modified RING finger, C3HGC3-type, found in RING finger and WD repeat domain-containing protein 3 (RFWD3) and similar proteins; RFWD3, also known as RING finger protein 201 (RNF201) or FLJ10520, is an E3 ubiquitin-protein ligase that forms a complex with Mdm2 and p53 to synergistically ubiquitinate p53 and acts as a positive regulator of p53 stability in response to DNA damage. It is phosphorylated by checkpoint kinase ATM/ATR and the phosphorylation mutant fails to stimulate p53 ubiquitination. RFWD3 also functions as a novel replication protein A (RPA)-associated protein involved in DNA replication checkpoint control. RFWD3 contains an N-terminal SQ-rich region followed by a RING finger domain that exhibits robust E3 ubiquitin ligase activity toward p53, a coiled-coil domain and three WD40 repeats in the C-terminus, the latter two of which may be responsible for protein-protein interaction. The RING finger in this family is a modified C3HGC3-type RING finger, but not a canonical C3H2C3-type RING-H2 finger or C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1386876290  15 CFICMEKLRDA---RLCP-HCSKLCCFSCIRRWLTEQRAQCPHCRAPLQLRELVN 65
Cdd:cd16450     5 CPICFEPWTSSgehRLVSlKCGHLFGYSCIEKWLKGKGKKCPQCNKKAKRSDIRP 59

Variant RING finger, HC subclass (C4C4-type), found in retinoblastoma-binding protein 6 (RBBP6) and similar proteins; RBBP6, also known as proliferation potential-related protein, protein P2P-R, retinoblastoma-binding Q protein 1 (RBQ-1), or p53-associated cellular protein of testis (PACT), is a nuclear E3 ubiquitin-protein ligase involved in multiple processes, such as the control of gene expression, mitosis, cell differentiation, and cell apoptosis. It plays a role in both promoting and inhibiting apoptosis in many human cancers, including esophageal, lung, hepatocellular, and colon cancers, familial myeloproliferative neoplasms, as well as in human immunodeficiency virus-associated nephropathy (HIVAN). It functions as an Rb- and p53-binding protein that plays an important role in chaperone-mediated ubiquitination and possibly in protein quality control. It acts as a scaffold protein to promote the assembly of the p53/TP53-MDM2 complex, resulting in an increase of MDM2-mediated ubiquitination and degradation of p53/TP53, and leading to both apoptosis and cell growth. It is also a double-stranded RNA-binding protein that plays a role in mRNA processing by regulating the human polyadenylation machinery and modulating expression of mRNAs with AU-rich 3' untranslated regions (UTRs). Moreover, RBBP6 ubiquitinates and destabilizes the transcriptional repressor ZBTB38 that negatively regulates transcription and levels of the MCM10 replication factor on chromatin. Furthermore, RBBP6 is involved in tunicamycin-induced apoptosis by mediating protein kinase (PKR) activation. RBBP6 contains an N-terminal ubiquitin-like domain and a C4C4-type RING finger, whose overall folding is similar to that of the typical C3HC4-type RING-HC finger. RBBP6 interacts with chaperones Hsp70 and Hsp40 through its N-terminal ubiquitin-like domain. It promotes the ubiquitination of p53 by Hdm2 in an E4-like manner through its RING finger. It also interacts directly with the pro-proliferative transcription factor Y-box-binding protein-1 (YB-1) via its RING finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1386876290  13 FRCFICMEKLRDARLCPHCSKLCCFSCIRRWLTEQRAQCPHCRAPLQLREL 63
Cdd:cd16620     4 LKCPICKDLMKDAVLTPCCGNSFCDECIRTALLEEDFTCPTCKEPDVSPDA 54

Ubiquitin-specific protease 21 (Ubp21p) family, MATH domain; composed of fungal proteins with similarity to Ubp21p of fission yeast. Ubp21p is a deubiquitinating enzyme that may be involved in the regulation of the protein kinase Prp4p, which controls the formation of active spliceosomes. Members of this family are similar to human HAUSP (Herpesvirus-associated ubiquitin-specific protease) in that they contain an N-terminal MATH domain and a C-terminal catalytic protease (C19 family) domain. HAUSP is also an ubiquitin-specific protease that specifically catalyzes the deubiquitylation of p53 and MDM2. The MATH domain of HAUSP contains the binding site for p53 and MDM2. Similarly, the MATH domain of members in this family may be involved in substrate binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290 277 DSATFVLENFSTLRQRadpVYSPPLQVSGLCWRLKVYPDGNGVVRgyYLSVFLE------LSAGLPETSKYEYRVEMVHQ 350
Cdd:cd03775     1 QSFTWRIKNWSELEKK---VHSPKFKCGGFEWRILLFPQGNSQTG--GVSIYLEphpeeeEKAPLDEDWSVCAQFALVIS 75

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1386876290 351 SCNDPTKNIIREFASDFEVGEC-WGYNRFFRLDLLA 385
Cdd:cd03775    76 NPGDPSIQLSNVAHHRFNAEDKdWGFTRFIELRKLA 111

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        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1386876290  13 FRCFICMEKLRDARLCpHCSKLCCFSCIRRWLTEQRAQCPHCRAPLQLREL 63
Cdd:cd16509     4 EECAICLDSLTNPVIT-PCAHVFCRRCICEVIQREKAKCPMCRAPLSASDL 53

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1386876290  15 CFICMEKLRDARLCP--HCSklCCFSCIRRWLtEQRAQCPHCRAPLQ 59
Cdd:pfam13920   5 CVICLDRPRNVVLLPcgHLC--LCEECAERLL-RKKKKCPICRQPIE 48

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1386876290  13 FRCFICMEKLRDARLCPHCSKLCCFSCIRRWlTEQRAQCPHCRAPL 58
Cdd:cd23130     1 DVCPICLDDPEDEAITLPCLHQFCYTCILRW-LQTSPTCPLCKTPV 45

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 1386876290  15 CFICMEKLRDARLCPhCSKLCCFSCIRRWLtEQRAQCPHCRAPLQ 59
Cdd:cd16561     5 CSICLEDLNDPVKLP-CDHVFCEECIRQWL-PGQMSCPLCRTELP 47

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 1386876290  15 CFICMEKLRDARLCPhCSKLCCFSCIRRWLtEQRAQCPHCRAPL 58
Cdd:cd16455     3 CAICWESMQSARKLP-CGHLFHNSCLRSWL-EQDTSCPTCRMSL 44

B-box-type 2 zinc finger found in tripartite motif-containing protein 14 (TRIM14) and similar proteins; TRIM14 is a mitochondrial adaptor that facilitates innate immune signaling. It also plays a critical role in tumor development. TRIM14 belongs to an unclassified TRIM (tripartite motif) family of proteins that do not have RING fingers and thus lack the characteristic tripartite (RING (R), B-box, and coiled coil (CC)) RBCC motif. It contains a Bbox2 zinc finger as well as a C-terminal SPRY/B30.2 domain. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1386876290  93 DKCENHHE-KLSVFCWTCKKCICHQCALWGGmHGGHTFKPLAEIY 136
Cdd:cd19768     1 RCCPEHKDrPLELFCKTCKRCVCALCPILGQ-HRGHDVRLIDEEA 44

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 1386876290  13 FRCFICMEKLRDA--RLCPHcskLCCFSCIRRWLTE--QRAQCPHCRA 56
Cdd:cd16743     1 FECNICLETARDAvvSLCGH---LFCWPCLHQWLETrpERQECPVCKA 45

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 1386876290  15 CFICMEKL--RDARLCPHCSklCCF--SCIRRWLTEQRAQCPHCR 55
Cdd:cd16448     1 CVICLEEFeeGDVVRLLPCG--HVFhlACILRWLESGNNTCPLCR 43

Modified RING finger, HC subclass (C2H2C4-type), found in E3 ubiquitin-protein ligase MDM2, protein MDM4 and similar proteins; MDM2 (also known as HDM2) and MDM4 (also known as MDMX or HDMX) are the primary p53 tumor suppressor negative regulators. They have non-redundant roles in the regulation of p53. MDM2 mainly functions to control p53 stability, while MDM4 controls p53 transcriptional activity. Both MDM2 and MDM4 contain an N-terminal p53-binding domain, a RanBP2-type zinc finger (zf-RanBP2) domain near the central acidic region, and a C-terminal modified C2H2C4-type RING-HC finger. Mdm2 can form homo-oligomers through its RING domain and displays E3 ubiquitin ligase activity that catalyzes the attachment of ubiquitin to p53 as an essential step in the regulation of its levels in cells. Despite its RING domain and structural similarity with MDM2, MDM4 does not homo-oligomerize and lacks ubiquitin-ligase function, but inhibits the transcriptional activity of p53. In addition, both their RING domains are responsible for the hetero-oligomerization, which is crucial for the suppression of P53 activity during embryonic development and the recruitment of E2 ubiquitin-conjugating enzymes. Moreover, MDM2 and MDM4 can be phosphorylated and destabilized in response to DNA damage stress. In response to ribosomal stress, MDM2-mediated p53 ubiquitination and degradation can be inhibited through the interaction with ribosomal proteins L5, L11, and L23. However, MDM4 is not bound to ribosomal proteins, suggesting its different response to regulation by small basic proteins such as ribosomal proteins and ARF.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1386876290  15 CFICMEKLRDARLCPHCS--KLCCFSCIRRWLtEQRAQCPHCRAPLQL 60
Cdd:cd16646     3 CVICLSRPRTAAIVHGKTghQVACYTCAKKLK-RRGKPCPVCRRPIQN 49

B-box-type 2 zinc finger found in tripartite motif-containing proteins, TRIM9, TRIM67 and similar proteins; This family includes a group of tripartite motif-containing proteins including TRIM9 and TRIM67, both of which belong to the C-I subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, consisting of three consecutive zinc-binding domains, a RING finger, Bbox1 and Bbox2, and a coiled coil region, as well as a COS (carboxyl-terminal subgroup one signature) box, a fibronectin type III (FN3) domain, and a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif. TRIM9 (the human ortholog of rat Spring), also known as RING finger protein 91 (RNF91), is a brain-specific E3 ubiquitin-protein ligase collaborating with an E2 ubiquitin conjugating enzyme UBCH5b. It plays an important role in the regulation of neuronal functions and participates in neurodegenerative disorders through its ligase activity. TRIM67, also termed TRIM9-like protein (TNL), is a protein selectively expressed in the cerebellum. It interacts with PRG-1, an important molecule in the control of hippocampal excitability dependent on presynaptic LPA2 receptor signaling, and 80K-H (also known as glucosidase II beta), a protein kinase C substrate. It negatively regulates Ras signaling in cell proliferation via degradation of 80K-H, leading to neural differentiation including neuritogenesis.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1386876290  94 KCENH-HEKLSVFCWTCKKCICHQCaLWGGMHGGHTFKPL 132
Cdd:cd19764     1 TCSEHpDEALSMYCLSCKVPVCYLC-LEDGRHSNHDVQAL 39

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.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
                  ....*....|....*....|....*....|....*....|....*..
gi 1386876290  13 FRCFICMEKLRDARLCPhCSKLCCFSCIRRWLTEQrAQCPHCRAPLQ 59
Cdd:TIGR00599  27 LRCHICKDFFDVPVLTS-CSHTFCSLCIRRCLSNQ-PKCPLCRAEDQ 71

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1386876290  13 FRCFICMEKLRDArLCPHCSKLCCFSCIRRWLTEQRAQ--CPHCRA 56
Cdd:cd16745     1 FECNICLDLAQDP-VVTLCGHLFCWPCLHKWLRRQSSQpeCPVCKA 45

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1386876290  13 FRCFICMEKLRDArLCPHCSKLCCFSCIRRWLTEQRAQ-CPHCRAPLQLRElVNC 66
Cdd:COG5574   216 YKCFLCLEEPEVP-SCTPCGHLFCLSCLLISWTKKKYEfCPLCRAKVYPKK-VII 268

B-box-type 2 zinc finger found in tripartite motif-containing protein 67 (TRIM67) and similar proteins; TRIM67, also termed TRIM9-like protein (TNL), is a protein selectively expressed in the cerebellum. It interacts with PRG-1, an important molecule in the control of hippocampal excitability dependent on presynaptic LPA2 receptor signaling, and 80K-H (also known as glucosidase II beta), a protein kinase C substrate. It negatively regulates Ras signaling in cell proliferation via degradation of 80K-H, leading to neural differentiation including neuritogenesis. TRIM67 belongs to the C-I 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 RING finger, Bbox1 and Bbox2, and a coiled coil region, as well as a COS (carboxyl-terminal subgroup one signature) box, the fibronectin type III domain and the SPRY/B30.2 domain positioned C-terminal to the RBCC domain. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1386876290  95 CENHH-EKLSVFCWTCKKCICHQCaLWGGMHGGHTFKPLAEIYE 137
Cdd:cd19827     3 CAEHElENYSMYCASCRTPVCYQC-LEEGKHAKHEVKALGAMWK 45

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 1386876290  11 EVFRCFICMEKLRDARLCPHCSKLCCFSCIRRWLTEQRAQCPHCRAPLQLRE 62
Cdd:cd16544     1 AELTCPVCQEVLKDPVELPPCRHIFCKACILLALRSSGARCPLCRGPVGKTE 52

RING finger, HC subclass, found in makorin-4 (MKRN4) and similar proteins; MKRN4, also known as makorin RING finger protein pseudogene 4, makorin RING finger protein pseudogene 5, RING finger protein 64 (RNF64), zinc finger protein 127-Xp (ZNF127-Xp), or zinc finger protein 127-like 1, is a new divergent member of the makorin protein family in vertebrates. It may have an ancestral gonad-specific function and maternal embryonic expression before duplication in vertebrates. MKRN4 contains typical arrays of one to four C3H1-type zinc fingers, a motif rich in Cys and His residues (CH) and a C3HC4-type RING-HC finger. The RING-HC finger of mammalian MKRN4 shows high sequence similarity with that of MKRN3, and is not included in this model.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1386876290  15 CFICMEKL--------RDARLCPHCSKLCCFSCIRRWLTEQRAQ------CPHCR 55
Cdd:cd16732     4 CGICMDKVyekahakeRVFGILPNCNHAFCVGCIKKWRKSKDFQnevikaCPQCR 58

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 1386876290  14 RCFICMEKLRDARLCPhCSKL-CCFSCIRRwLTEQRAQCPHCRAPLQ 59
Cdd:cd23129     4 ECVVCMDAPRDAVCVP-CGHVaGCMSCLKA-LMQSSPLCPICRAPVR 48

Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) family, N-terminal MATH (TRAF-like) domain; composed of proteins similar to human HAUSP, an enzyme that specifically catalyzes the deubiquitylation of p53 and MDM2, hence playing an important role in the p53-MDM2 pathway. It contains an N-terminal TRAF-like domain and a C-terminal catalytic protease (C19 family) domain. The tumor suppressor p53 protein is a transcription factor that responds to many cellular stress signals and is regulated primarily through ubiquitylation and subsequent degradation. MDM2 is a RING-finger E3 ubiquitin ligase that promotes p53 ubiquitinylation. p53 and MDM2 bind to the same site in the N-terminal TRAF-like domain of HAUSP in a mutually exclusive manner. HAUSP also interacts with the Epstein-Barr nuclear antigen 1 (EBNA1) protein of the Epstein-Barr virus (EBV), which efficiently immortalizes infected cells predisposing the host to a variety of cancers. EBNA1 plays several important roles in EBV latent infection and cellular transformation. It binds the same pocket as p53 in the HAUSP TRAF-like domain. Through interactions with p53, MDM2 and EBNA1, HAUSP plays a role in cell proliferation, apoptosis and EBV-mediated immortalization.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1386876290 281 FVLENFSTLRQRadpVYSPPLQVSGLCWRLKVYPDGNGVVRGYYLSV--FLELSaglPETSKYEYRV----EMVHQSCND 354
Cdd:cd03772     7 FTVERFSRLSES---VLSPPCFVRNLPWKIMVMPRNYPDRNPHQKSVgfFLQCN---AESDSTSWSChaqaVLRIINYKD 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1386876290 355 PTKNIIREFASDFEVGEC-WGYNRFFRLDLLANE--GYLnrQNDTVILRFQV 403
Cdd:cd03772    81 DEPSFSRRISHLFFSKENdWGFSNFMTWSEVTDPekGFI--EDDTITLEVYV 130

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 1386876290  14 RCFICMEKLRDARLCPHCSKLCCFSCIRRWLtEQRAQCPHC 54
Cdd:pfam13923   1 MCPICMDMLKDPSTTTPCGHVFCQDCILRAL-EASNECPLC 40

B-box-type 2 zinc finger found in tripartite motif-containing protein 72 (TRIM72) and similar proteins; TRIM72, also known as Mitsugumin-53 (MG53), is a muscle-specific protein that plays a central role in cell membrane repair by nucleating the assembly of the repair machinery at muscle injury sites. It is required in repair of alveolar epithelial cells under plasma membrane stress failure. It interacts with dysferlin to regulate sarcolemmal repair. Upregulation of TRIM72 develops obesity, systemic insulin resistance, dyslipidemia, and hyperglycemia, as well as induces diabetic cardiomyopathy through transcriptional activation of peroxisome proliferation-activated receptor alpha (PPAR-alpha) signaling pathway. Compensation for the absence of AKT signaling by ERK signaling during TRIM72 overexpression leads to pathological hypertrophy. Moreover, TRIM72 functions as a novel negative feedback regulator of myogenesis via targeting insulin receptor substrate-1 (IRS-1). It is transcriptionally activated by the synergism of myogenin (MyoD) and myocyte enhancer factor 2 (MEF2). TRIM72 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 RING 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. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1386876290  93 DKCENHHEKLSVFCWTCKKCICHQCALWGGmHGGHTFKPLAE 134
Cdd:cd19797     1 GHCEEHLDPLSVYCEQDRALICGVCASLGK-HKGHNIITAAE 41

RING finger, HC subclass, found in the makorin (MKRN) proteins; The MKRN protein subfamily includes ribonucleoproteins that are characterized by a variety of zinc-finger motifs, including typical arrays of one to four C3H1-type zinc fingers and a C3HC4-type RING-HC finger. Another motif rich in Cys and His residues (CH), with so far unknown function, is also generally present in MKRN proteins. MKRN proteins may have E3 ubiquitin ligase activity.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1386876290  15 CFICMEK-LRDAR---LCPHCSKLCCFSCIRRW------LTEQRAQCPHCR 55
Cdd:cd16521     3 CGICMEVvLEKERrfgILSNCNHVFCLECIREWrsskdfENSIVRSCPICR 53

RING finger, HC subclass, found in Saccharomyces cerevisiae radiation sensitivity protein 18 (RAD18) and similar proteins; RAD18, also called RING-type E3 ubiquitin transferase RAD18, acts as a postreplication repair E3 ubiquitin-protein ligase that associates with the E2 ubiquitin conjugating enzyme UBC2/RAD6 to form the UBC2-RAD18 ubiquitin ligase complex involved in postreplicative repair (PRR) of damaged DNA. The UBC2-RAD18 complex cooperates with RAD5 and the UBC13-MMS2 dimer to attach mono-ubiquitin chains on 'Lys-164' of POL30, which is necessary for PRR. The UBC2-RAD18 complex is also involved in prevention of spontaneous mutations caused by 7,8-dihydro-8-oxoguanine. RAD18 is an E3 RING-finger protein belonging to the UBC2/RAD6 epistasis group. It contains a typical C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1386876290  13 FRCFICMEKLRDARLCPhCSKLCCFSCIRRWLTEQrAQCPHCRAPLQLREL 63
Cdd:cd23148     4 LRCHICKDLLKAPMRTP-CNHTFCSFCIRTHLNND-ARCPLCKAEVTESGL 52

RING finger, H2 subclass, found in RING finger protein 167 (RNF167) and similar proteins; RNF167, also known as RING105, is an endosomal/lysosomal E3 ubiquitin-protein ligase involved in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) ubiquitination. It ubiquitinates AMPA-type glutamate receptor subunit GluA2 and regulates its surface expression, and thus acts as a selective regulator of AMPAR-mediated neurotransmission. It acts as an endosomal membrane protein which ubiquitylates vesicle-associated membrane protein 3 (VAMP3) and regulates endosomal trafficking. Moreover, RNF167 plays a role in the regulation of TSSC5 (tumor-suppressing subchromosomal transferable fragment cDNA, also known as ORCTL2/IMPT1/BWR1A/SLC22A1L), which can function in concert with the ubiquitin-conjugating enzyme UbcH6. RNF167 is widely conserved in metazoans and contains an N-terminal signal peptide, a protease-associated (PA) domain, two transmembrane domains (TM1 and TM2), and a C-terminal C3H2C3-type RING-H2 finger domain followed by a putative PEST sequence.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1386876290  15 CFICMEKLRDA---RLCPhCSKLCCFSCIRRWLTEQRAQCPHCR 55
Cdd:cd16797     3 CAICLDEYEEGdklRVLP-CSHAYHSKCVDPWLTQTKKTCPVCK 45

RING finger, HC subclass, found in checkpoint with forkhead and RING finger domains protein (CHFR); CHFR, also known as RING finger protein 196 (RNF196), is a checkpoint protein that delays entry into mitosis in response to stress. It functions as an E3 ubiquitin ligase that ubiquitinates and degrades its target proteins, such as Aurora-A, Plk1, Kif22, and PARP-1, which are critical for proper mitotic transitions. It also plays an important role in cell cycle progression and tumor suppression, and is negatively regulated by SUMOylation-mediated proteasomal ubiquitylation. Moreover, CHFR is involved in the early stage of the DNA damage response, which mediates the crosstalk between ubiquitination and poly-ADP-ribosylation. CHFR contains a fork head associated (FHA) domain and a C3HC4-type RING-HC finger.