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 1958659695 273 VPSYDSATFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHQSc 352
Cdd:cd03773     1 IPPYDSATFTLENFSTLRQSADPVYSDPLNVDGLCWRLKVYPDGNGEVRGNFLSVFLELCSGLGEASKYEYRVEMVHQA- 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1958659695 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 1958659695  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 1958659695 273 VPSYDSATFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHQSc 352
Cdd:cd03773     1 IPPYDSATFTLENFSTLRQSADPVYSDPLNVDGLCWRLKVYPDGNGEVRGNFLSVFLELCSGLGEASKYEYRVEMVHQA- 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1958659695 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 1958659695  93 DKCENHHEKLSVFCWTCKKCICHQCALWGGMHGGHTFKPL 132
Cdd:cd19779     1 DKCETHNEKLSVYCWTCKKCICHQCALWGGTHSGHTFKPL 40

meprin and TRAF homology;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958659695  284 ENFSTLRqRADPVYSPPLQVSGLCWRLKVYPDGNgvvrgyYLSVFLELSAGLPETSKY--EYRVEMVHQSCNDptKNIIR 361
Cdd:smart00061   7 KNVSRLE-EGESYFSPSEEHFNIPWRLKIYRKNG------FLSLYLHCEKEECDSRKWsiEAEFTLKLVSQNG--KSLSK 77

                           90
                   ....*....|....*...
gi 1958659695  362 EFASDFEVGECWGYNRFF 379
Cdd:smart00061  78 KDKHVFEKPSGWGFSKFI 95

B-Box-type zinc finger;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1958659695   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 1958659695   15 CFICMEKLRDARLCPHCSKLCCFSCIRRWLTEQRAQCPHC 54
Cdd:smart00184   1 CPICLEEYLKDPVILPCGHTFCRSCIRKWLESGNNTCPIC 40

N1R/p28-like protein; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958659695  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 1958659695  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 1958659695 132 LAEIYEQhVTKVNEEVAKLRRRLMELISLVQEV--ERN---------VEAVRNAKDER------VREIRNAVEMMIARLD 194
Cdd:COG1340    10 LEELEEK-IEELREEIEELKEKRDELNEELKELaeKRDelnaqvkelREEAQELREKRdelnekVKELKEERDELNEKLN 88

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1958659695 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 1958659695 273 VPSYDSATFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHQSc 352
Cdd:cd03773     1 IPPYDSATFTLENFSTLRQSADPVYSDPLNVDGLCWRLKVYPDGNGEVRGNFLSVFLELCSGLGEASKYEYRVEMVHQA- 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1958659695 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 1958659695 280 TFVLENFSTLRQRADPVYSPPLQVSGLCWRLKVYPDGNGvVRGYYLSVFLELSAGLPETS----KYEYRVEMVHQscnDP 355
Cdd:cd00121     2 KHTWKIVNFSELEGESIYSPPFEVGGYKWRIRIYPNGDG-ESGDYLSLYLELDKGESDLEkwsvRAEFTLKLVNQ---NG 77

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1958659695 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 1958659695  13 FRCFICMEKLRDARLCPHCSKLCCFSCIRRWLTEQRAQCPHCR 55
Cdd:cd16619     1 FRCFICMEKLRDPRLCPHCSKLFCKGCIRRWLSEQRSSCPHCR 43

B-box zinc finger;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1958659695  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 1958659695  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 1958659695  13 FRCFICMEKLRDARLCPhCSKLCCFSCIRRWLTEqRAQCPHCRAPLQLRELV 64
Cdd:cd16527     1 RKCSLCLEERRHPTATP-CGHLFCWSCITEWCNE-KPECPLCREPFQPQRLV 50

Tumor Necrosis Factor Receptor (TNFR)-Associated Factor (TRAF) family, TRAF domain, C-terminal MATH subdomain; TRAF molecules serve as adapter proteins that link cell surface TNFRs and receptors of the interleukin-1/Toll-like family to downstream kinase signaling 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. There are at least six mammalian and three Drosophila proteins containing TRAF domains. The mammalian TRAFs display varying expression profiles, indicating independent and cell type-specific regulation. They display distinct, as well as overlapping functions and interactions with receptors. Most TRAFs, except TRAF1, share N-terminal homology and contain a RING domain, multiple zinc finger domains, and a TRAF domain. TRAFs form homo- and heterotrimers through its TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded beta-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958659695 283 LENFSTLRQRAD-----PVYSPPLQVSG----LCwrLKVYPDGNGVVRGYYLSVFL-----ELSAGLPETSKYEYRVEMV 348
Cdd:cd00270     7 IKDYSRKLQEAVagsntVLYSPPFYTSRygykLC--LRLYLNGDGTGKGTHLSLFVhvmkgEYDALLEWPFRGKITLTLL 84

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958659695 349 HQSCNDPTKNIIREFASD-----FEVGEC------WGYNRFFRLDLLANEGYLnrQNDTVILRFQV 403
Cdd:cd00270    85 DQSDDSKRKHITETFMPDpnssaFQRPPTgennigFGYPEFVPLEKLESRGYV--KDDTLFIKVEV 148

RING finger, HC subclass, found in postreplication repair protein RAD18 and similar proteins; RAD18, also known as HR18 or RING finger protein 73 (RNF73), is an E3 ubiquitin-protein ligase involved in post replication repair of UV-damaged DNA via its recruitment to stalled replication forks. It associates to the E2 ubiquitin conjugating enzyme UBE2B to form the UBE2B-RAD18 ubiquitin ligase complex involved in mono-ubiquitination of DNA-associated PCNA on K164. It also interacts with another E2 ubiquitin conjugating enzyme RAD6 to form a complex that monoubiquitinates proliferating cell nuclear antigen at stalled replication forks in DNA translesion synthesis. Moreover, Rad18 is a key factor in double-strand break DNA damage response (DDR) pathways via its association with K63-linked polyubiquitylated chromatin proteins. It can function as a mediator for DNA damage response signals to activate the G2/M checkpoint in order to maintain genome integrity and cell survival after ionizing radiation (IR) exposure. RAD18 contains a C3HC4-type RING-HC finger, a ubiquitin-binding zinc finger domain (UBZ), a SAP (SAF-A/B, Acinus and PIAS) domain, and a RAD6-binding domain (R6BD).

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1958659695   9 IAEVFRCFICMEKLRDARLCPHCSKLCCFSCIRRWLTEqRAQCPHCRAPLQLREL 63
Cdd:cd16529     1 LDDLLRCPICFEYFNTAMMITQCSHNYCSLCIRRFLSY-KTQCPTCRAAVTESDL 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 1958659695 277 DSATFVLENFSTLRQRadpVYSPPLQVSGLCWRLKVYPDGNGVVRgyYLSVFLE------LSAGLPETSKYEYRVEMVHQ 350
Cdd:cd03775     1 QSFTWRIKNWSELEKK---VHSPKFKCGGFEWRILLFPQGNSQTG--GVSIYLEphpeeeEKAPLDEDWSVCAQFALVIS 75

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1958659695 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 1958659695  13 FRCFICMEKLRDARLCpHCSKLCCFSCIRRWLTEQRAQCPHCRAPLQLREL 63
Cdd:cd16509     4 EECAICLDSLTNPVIT-PCAHVFCRRCICEVIQREKAKCPMCRAPLSASDL 53

Zinc finger, C3HC4 type (RING finger);

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1958659695  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 1958659695  13 FRCFICMEKLRDARLCPHCSKLCCFSCIRRWlTEQRAQCPHCRAPL 58
Cdd:cd23130     1 DVCPICLDDPEDEAITLPCLHQFCYTCILRW-LQTSPTCPLCKTPV 45

N1R/p28-like protein; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1958659695  15 CFICMEKLRDAR-------LCPHCSKLCCFSCIRRWlTEQRAQCPHCRAP 57
Cdd:PHA02929  177 CAICMEKVYDKEiknmyfgILSNCNHVFCIECIDIW-KKEKNTCPVCRTP 225

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 1958659695  93 DKCENHHE-KLSVFCWTCKKCICHQCALWGGmHGGHTFKPLAEIY 136
Cdd:cd19768     1 RCCPEHKDrPLELFCKTCKRCVCALCPILGQ-HRGHDVRLIDEEA 44

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 1958659695  15 CFICMEKLRDARLCPhCSKLCCFSCIRRWLTEQRAQCPHCR 55
Cdd:cd16502     4 CKICAENDKDVRIEP-CGHLLCTPCLTSWQDSDGQTCPFCR 43

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1958659695  15 CFICMEKLRD--ARLCPhCSKLCCFSCIRRWlTEQRAQCPHCRAP 57
Cdd:cd16574     4 CPICLDRFENekAFLDG-CFHAFCFTCILEW-SKVKNECPLCKQP 46

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1958659695  15 CFICMEKLRDARLCPhCSKLCCFSCIRRWLTEQRAQCPHCRAPLQLRELVN 65
Cdd:cd16710    16 CKICAERDKDVRIEP-CGHLLCSCCLAAWQHSDSQTCPFCRCEIKGREAVS 65

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 1958659695  13 FRCFICMEKLRDARLCPhCSKLCCFSCIRRWLTE--QRAQCPHCR 55
Cdd:cd16534     1 FECNICLDTASDPVVTM-CGHLFCWPCLYQWLETrpDRQTCPVCK 44

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 1958659695  94 KCENH-HEKLSVFCWTCKKCICHQCaLWGGMHGGHTFKPL 132
Cdd:cd19764     1 TCSEHpDEALSMYCLSCKVPVCYLC-LEDGRHSNHDVQAL 39

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 1958659695  15 CFICMEKL--RDARLCPHCSklCCF--SCIRRWLTEQRAQCPHCR 55
Cdd:cd16448     1 CVICLEEFeeGDVVRLLPCG--HVFhlACILRWLESGNNTCPLCR 43

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 1958659695  13 FRCFICMEKLRDArLCPHCSKLCCFSCIRRWLTEQRAQ--CPHCRA 56
Cdd:cd16745     1 FECNICLDLAQDP-VVTLCGHLFCWPCLHKWLRRQSSQpeCPVCKA 45

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1958659695  15 CFICMEKLRdarlcPHCSKLCC-----FSCIRRWLTEQRaQCPHCR 55
Cdd:cd16479     4 CIICREEMT-----VGAKKLPCghifhLSCLRSWLQRQQ-TCPTCR 43

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 1958659695  95 CENHH-EKLSVFCWTCKKCICHQCaLWGGMHGGHTFKPLAEIYE 137
Cdd:cd19827     3 CAEHElENYSMYCASCRTPVCYQC-LEEGKHAKHEVKALGAMWK 45

B-box-type 2 zinc finger found in B box and SPRY domain-containing protein (BSPRY) and similar proteins; BSPRY is a regulatory protein for maintaining calcium homeostasis. It may regulate epithelial calcium transport by inhibiting TRPV5 activity. BSPRY is composed of a B-box, an alpha-helical coiled coil and a SPRY domain. The B-box motif shows high sequence similarity with B-Box-type zinc finger 2 found in tripartite motif-containing proteins (TRIMs). The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 1958659695  93 DKCENHHEKLSVFCWTCKKCICHQCALWGGMHgGHTFKPLAE 134
Cdd:cd19834     1 DLCPDHELELDWFCSTERRLVCAQCASLGTCR-GHRVTPLEE 41

The Bin/Amphiphysin/Rvs (BAR) domain of GTPase Regulator Associated with Focal adhesion kinase; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. GTPase Regulator Associated with Focal adhesion kinase (GRAF), also called Rho GTPase activating protein 26 (ARHGAP26), is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domain of GRAF directly interacts with its Rho GAP domain and inhibits its activity. Autoinhibited GRAF is capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958659695 158 ISLVQEVERNVEAVRNAKDERVREIRNAVEMMIARLDTQLKNKLITLMGQKTSLTQETELL---------------ESLL 222
Cdd:cd07636    63 ICIARSLQEFAAVLRNLEDERTRMIENASEVLITPLEKFRKEQIGAAKEAKKKYDKETEKYcavlekhlnlsskkkESQL 142

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1958659695 223 QEVEHQLRSCsKSELISKSAEILMMFQQVHRKPMASFV 260
Cdd:cd07636   143 HEADSQVDLV-RQHFYEVSLEYVFKVQEVQERKMFEFV 179

RING finger, H2 subclass, found in Arabidopsis thaliana RING-H2 finger A1a (RHA1A), A1b (RHA1B) and similar proteins; This subfamily includes Arabidopsis thaliana RHA1A, RHA1B and XERICO. RHA1A is a probable E3 ubiquitin-protein ligase that may possess E3 ubiquitin ligase activity in vitro. RHA1B possesses E3 ubiquitin-protein ligase activity when associated with the E2 enzyme UBC8 in vitro. XERICO functions on abscisic acid homeostasis at post-translational level, probably through ubiquitin/proteasome-dependent substrate-specific degradation. Members of this subfamily contain a C3H2C3-type RING-H2 finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1958659695  14 RCFICMEKLRDA---RLCPHCSKLCCFSCIRRWLTEQRAQCPHCRAPL 58
Cdd:cd23121     3 CCAICLSDFNSDeklRQLPKCGHIFHHHCLDRWIRYNKITCPLCRADL 50

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 1958659695  14 RCFICMEKLRDARLCPhCSKL-CCFSCIRRwLTEQRAQCPHCRAPLQ 59
Cdd:cd23129     4 ECVVCMDAPRDAVCVP-CGHVaGCMSCLKA-LMQSSPLCPICRAPVR 48

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 1958659695  93 DKCENHHEKLSVFCWTCKKCICHQCALWGGmHGGHTFKPLAE 134
Cdd:cd19797     1 GHCEEHLDPLSVYCEQDRALICGVCASLGK-HKGHNIITAAE 41

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
                  ....*....|....*....|....*....|....*....|....*...
gi 1958659695  15 CFICMEKLRDARLCPhCSKLCCFSCIRRWLTEQRAQCPHCRAPLQLRE 62
Cdd:cd16708    24 CKICAENDKDVKIEP-CGHLMCTSCLTSWQESEGQGCPFCRCEIKGTE 70

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 1958659695  15 CFICMEK-LRDAR---LCPHCSKLCCFSCIRRW------LTEQRAQCPHCR 55
Cdd:cd16521     3 CGICMEVvLEKERrfgILSNCNHVFCLECIREWrsskdfENSIVRSCPICR 53

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

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1958659695   1 MDEQSVESIAEVfRCFICME---KLRDARLCPhCSKLCCFSCIRRWLTEQRAQCPHCRAPL 58
Cdd:COG5540   313 SIERAVEADKGV-ECAICMSnfiKNDRLRVLP-CDHRFHVGCVDKWLLGYSNKCPVCRTAI 371

Speckle-type POZ protein (SPOP) family, MATH domain; composed of proteins with similarity to human SPOP. SPOP was isolated as a novel antigen recognized by serum from a scleroderma patient, whose overexpression in COS cells results in a discrete speckled pattern in the nuclei. It contains an N-terminal MATH domain and a C-terminal BTB (also called POZ) domain. Together with Cul3, SPOP constitutes an ubiquitin E3 ligase which is able to ubiquitinate the PcG protein BMI1, the variant histone macroH2A1 and the death domain-associated protein Daxx. Therefore, SPOP may be involved in the regulation of these proteins and may play a role in transcriptional regulation, apoptosis and X-chromosome inactivation. Cul3 binds to the BTB domain of SPOP whereas Daxx and the macroH2A1 nonhistone region have been shown to bind to the MATH domain. Both MATH and BTB domains are necessary for the nuclear speckled accumulation of SPOP. There are many proteins, mostly uncharacterized, containing both MATH and BTB domains from C. elegans and plants which are excluded from this family.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958659695 283 LENFSTLRQRADPVYSPPLQVSG----LCWRLKVYPDGNGVVRGYYLSVFLELSAGLPETSKYEYRVEMVHqSCNDPTKN 358
Cdd:cd03774    11 ISNFSFCREEMGEVIKSSTFSSGandkLKWCLRVNPKGLDEESKDYLSLYLLLVSCPKSEVRAKFKFSILN-AKGEETKA 89

                          90       100
                  ....*....|....*....|....*....
gi 1958659695 359 IIREFASDFEVGECWGYNRFFRLDLLANE 387
Cdd:cd03774    90 MESQRAYRFVQGKDWGFKKFIRRDFLLDE 118