SPRY domain; SPRY domains, first identified in the SP1A kinase of Dictyostelium and rabbit Ryanodine receptor (hence the name), are homologous to B30.2. SPRY domains have been identified in at least 11 protein families, covering a wide range of functions, including regulation of cytokine signaling (SOCS), RNA metabolism (DDX1 and hnRNP), immunity to retroviruses (TRIM5alpha), intracellular calcium release (ryanodine receptors or RyR) and regulatory and developmental processes (HERC1 and Ash2L). B30.2 also contains residues in the N-terminus that form a distinct PRY domain structure; i.e. B30.2 domain consists of PRY and SPRY subdomains. B30.2 domains comprise the C-terminus of three protein families: BTNs (receptor glycoproteins of immunoglobulin superfamily); several TRIM proteins (composed of RING/B-box/coiled-coil or RBCC core); Stonutoxin (secreted poisonous protein of the stonefish Synanceia horrida). TRIM/RBCC proteins are involved in a variety of processes, including apoptosis, cell cycle regulation, cell growth, senescence, viral response, meiosis, cell differentiation, and vesicular transport. Genes belonging to this family are implicated in several human diseases that vary from cancer to rare genetic syndromes. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site. While SPRY domains are evolutionarily ancient, B30.2 domains are a more recent adaptation where the SPRY/PRY combination is a possible component of immune defense. Mutations found in the SPRY-containing proteins have shown to cause Mediterranean fever and Opitz syndrome.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLF-LECLRKDDHYI----LITRIggeHYIEKPvGQVG 403
Cdd:cd13733   46 GSEGFSSGRHYWEVEVGGKTDWDLGVARESVNRKGKITLSPENGYwTVGLRNGNEYKaltsPSTPL---SLREKP-QKVG 121

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 283046820 404 VFLDCEGGYVSFVDVAKSSLILSYSpGTFHCAVRPFFS 441
Cdd:cd13733  122 VFLDYEEGQVSFYNVDDGSHIYTFT-DCFTEKLYPYFS 158

PRY/SPRY domain in tripartite motif-containing (TRIM) proteins, including TRIM5, TRIM6, TRIM7, TRIM10, TRIM11, TRIM17, TRIM20, TRIM21, TRIM27, TRIM35, TRIM38, TRIM41, TRIM50, TRIM58, TRIM60, TRIM62, TRIM69, TRIM72, NF7 and bloodthirsty; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several Class IV TRIM proteins, including TRIM7, TRIM35, TRIM41, TRIM50, TRIM62, TRIM69, TRIM72, TRIM protein NF7 and bloodthirsty (bty). TRIM7 interacts with glycogenin and stimulates its self-glucosylating activity via its SPRY domain. TRIM35 may play a role as a tumor suppressor and is implicated in the cell death mechanism. TRIM41 is localized to speckles in the cytoplasm and nucleus, and functions as an E3 ligase that catalyzes the ubiquitin-mediated degradation of protein kinase C. TRIM50, an E3 ubiquitin ligase, is deleted in Williams-Beuren (WBS) syndrome, a multi-system neurodevelopmental disorder caused by the deletion of contiguous genes at chromosome region 7q11.23. TRIM62 is involved in the morphogenesis of the mammary gland; loss of TRIM62 gene expression in breast is associated with increased risk of recurrence in early-onset breast cancer. TRIM69 is a novel testis E3 ubiquitin ligase that may function to ubiquitinate its particular substrates during spermatogenesis. In humans, TRIM69 localizes in the cytoplasm and nucleus, and requires an intact RING finger domain to function. TRIM protein NF7, which also contains a chromodomain (CHD) at the N-terminus and an RFP (Ret finger protein)-like domain at the C-terminus, is required for its association with transcriptional units of RNA polymerase II which is mediated by a trimeric B box. In Xenopus oocyte, xNF7 has been identified as a nuclear microtubule-associated protein (MAP) whose microtubule-bundling activity, but not E3-ligase activity, contributes to microtubule organization and spindle integrity. Bloodthirsty (bty) is a novel gene identified in zebrafish and has been shown to likely play a role in in regulation of the terminal steps of erythropoiesis. TRIM72 has been shown to perform a critical function in membrane repair following acute muscle injury by nucleating the assembly of the repair machinery at injury sites. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLF-LECLRKDDHYI----LITRIggeHYIEKPvGQVG 403
Cdd:cd13733   46 GSEGFSSGRHYWEVEVGGKTDWDLGVARESVNRKGKITLSPENGYwTVGLRNGNEYKaltsPSTPL---SLREKP-QKVG 121

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 283046820 404 VFLDCEGGYVSFVDVAKSSLILSYSpGTFHCAVRPFFS 441
Cdd:cd13733  122 VFLDYEEGQVSFYNVDDGSHIYTFT-DCFTEKLYPYFS 158

Domain in SPla and the RYanodine Receptor; Domain of unknown function. Distant homologues are domains in butyrophilin/marenostrin/pyrin homologues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820   335 RGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVaTPTDLFLECLRkDDHYILITRIGGEHYIEKPVGQ---VGVFLDCEGG 411
Cdd:smart00449   1 SGRHYFEVEIGDGGHWRVGVATKSVPRGYFAL-LGEDKGSWGYD-GDGGKKYHNSTGPEYGLPLQEPgdvIGCFLDLEAG 78

                           90       100       110
                   ....*....|....*....|....*....|
gi 283046820   412 YVSFVDVAKSSLILSYSPGTFHCAVRPFFS 441
Cdd:smart00449  79 TISFYKNGKYLHGLAFFDVKFSGPLYPAFS 108

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820  337 KYYWEVDLkDYRR---WTVGVCKDPW-LRGRSYVATPTDLFLECLRKDDHYILITrigGEHYIEKPVGQ---VGVFLDCE 409
Cdd:pfam00622   1 RHYFEVEI-FGQDgggWRVGWATKSVpRKGERFLGDESGSWGYDGWTGKKYWAST---SPLTGLPLFEPgdvIGCFLDYE 76

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 283046820  410 GGYVSFVDVAKsSLILSYSPGTFHCAVRPFFSAVY 444
Cdd:pfam00622  77 AGTISFTKNGK-SLGYAFRDVPFAGPLFPAVSLGA 110

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        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 283046820    9 PQEETLTCSICQGIFMNPVYLKCGHKFCEACLllfQEDIKFPAYCPMCMQPFnQE 63
Cdd:TIGR00599  22 PLDTSLRCHICKDFFDVPVLTSCSHTFCSLCI---RRCLSNQPKCPLCRAED-QE 72

B-box zinc finger;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 283046820   88 SEEHKCVTHKAKKMI-FCDKSKILLCHLCsDSQEHSGHTHCSI 129
Cdd:pfam00643   1 SKERLCPEHEEEPLTlYCNDCQELLCEEC-SVGEHRGHTVVPL 42

PRY/SPRY domain in tripartite motif-containing (TRIM) proteins, including TRIM5, TRIM6, TRIM7, TRIM10, TRIM11, TRIM17, TRIM20, TRIM21, TRIM27, TRIM35, TRIM38, TRIM41, TRIM50, TRIM58, TRIM60, TRIM62, TRIM69, TRIM72, NF7 and bloodthirsty; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several Class IV TRIM proteins, including TRIM7, TRIM35, TRIM41, TRIM50, TRIM62, TRIM69, TRIM72, TRIM protein NF7 and bloodthirsty (bty). TRIM7 interacts with glycogenin and stimulates its self-glucosylating activity via its SPRY domain. TRIM35 may play a role as a tumor suppressor and is implicated in the cell death mechanism. TRIM41 is localized to speckles in the cytoplasm and nucleus, and functions as an E3 ligase that catalyzes the ubiquitin-mediated degradation of protein kinase C. TRIM50, an E3 ubiquitin ligase, is deleted in Williams-Beuren (WBS) syndrome, a multi-system neurodevelopmental disorder caused by the deletion of contiguous genes at chromosome region 7q11.23. TRIM62 is involved in the morphogenesis of the mammary gland; loss of TRIM62 gene expression in breast is associated with increased risk of recurrence in early-onset breast cancer. TRIM69 is a novel testis E3 ubiquitin ligase that may function to ubiquitinate its particular substrates during spermatogenesis. In humans, TRIM69 localizes in the cytoplasm and nucleus, and requires an intact RING finger domain to function. TRIM protein NF7, which also contains a chromodomain (CHD) at the N-terminus and an RFP (Ret finger protein)-like domain at the C-terminus, is required for its association with transcriptional units of RNA polymerase II which is mediated by a trimeric B box. In Xenopus oocyte, xNF7 has been identified as a nuclear microtubule-associated protein (MAP) whose microtubule-bundling activity, but not E3-ligase activity, contributes to microtubule organization and spindle integrity. Bloodthirsty (bty) is a novel gene identified in zebrafish and has been shown to likely play a role in in regulation of the terminal steps of erythropoiesis. TRIM72 has been shown to perform a critical function in membrane repair following acute muscle injury by nucleating the assembly of the repair machinery at injury sites. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLF-LECLRKDDHYI----LITRIggeHYIEKPvGQVG 403
Cdd:cd13733   46 GSEGFSSGRHYWEVEVGGKTDWDLGVARESVNRKGKITLSPENGYwTVGLRNGNEYKaltsPSTPL---SLREKP-QKVG 121

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 283046820 404 VFLDCEGGYVSFVDVAKSSLILSYSpGTFHCAVRPFFS 441
Cdd:cd13733  122 VFLDYEEGQVSFYNVDDGSHIYTFT-DCFTEKLYPYFS 158

PRY/SPRY domain of tripartite motif-binding protein 38 (TRIM38), also known as Ring finger protein 15 (RNF15); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM38, which is also known as RING finger protein 15 (RNF15) or RORET. TRIM38 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM38 has been shown to act as a suppressor in TOLL-like receptor (TLR)-mediated interferon (IFN)-beta induction by promoting degradation of TRAF6 and NAP1 through the ubiquitin-proteasome system. Another study has shown that TRIM38 may act as a novel negative regulator for TLR3-mediated IFN-beta signaling by targeting TRIF for degradation. TRIM38 has been identified as a critical negative regulator in TNFalpha- and IL-1beta-triggered activation of NF-kappaB and MAP Kinases (MAPKs); it causes degradation of two essential cellular components, TGFbeta-associated kinase 1 (TAK1)-associating chaperones 2 and 3 (TAB2/3). The degradation is promoted through a lysosomal-dependent pathway, which requires the C-terminal PRY-SPRY of TRIM38. Enterovirus 71 infection induces degradation of TRIM38, suggesting that TRIM38 may play a role in viral infections.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLFLEC-LRKDDHYILITRIGGE-HYIEKPVgQVGVFL 406
Cdd:cd15815   59 GCEGFTSGRHYFEVDVGEGTGWDVGVCLENVQRGFGMKQEPEFGFWTIrLCEEDGYVALTSPPTPlPLREKPL-VVGVFL 137

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 283046820 407 DCEGGYVSFVDVAKSSLILSYSPGTFHCAVRPFFSaVY 444
Cdd:cd15815  138 DYEAGLVSFYNMTTGSHIFTFPKASFSDTLRPYFQ-VY 174

PRY/SPRY domain in tripartite motif-containing protein 27 (TRIM27), also known as RING finger protein 76 (RNF76); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM27, also known as RING finger protein 76 (RNF76) or RET finger protein (RFP). TRIM27 domain is composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It is highly expressed in the spleen, thymus and in cells of the hematopoietic compartment. TRIM27 exhibits either nuclear or cytosolic localization depending on the cell type. TRIM27 negatively regulates nucleotide-binding oligomerization domain containing 2 (NOD2)-mediated signaling by proteasomal degradation of NOD2, suggesting that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases such as Crohn's. High expression of TRIM27 is observed in several human cancers, including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Also, TRIM27 forms an oncogenic fusion protein with Ret proto-oncogene. It is involved in different stages of spermatogenesis and its significant expression in male germ cells and seminomas, suggests that TRIM27 may be associated with the regulation of testicular germ cell proliferation and histological-type of germ cell tumors. TRIM27 could also be a predictive marker for chemoresistance in ovarian cancer patients. In the neurotoxin model of Parkinson's disease (PD), deficiency of TRIM27 decreases apoptosis and protects dopaminergic neurons, making TRIM27 an effective potential target during the treatment of PD.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLFLEC-LRKDDHYILITRIGGEHYIEKPVGQVGVFLD 407
Cdd:cd15814   48 GSPCFIAGRHYWEVEVGDKAKWTIGVCEDSVCRKGGVTSAPQNGFWAVsLWYGKEYWALTSPMTALPLRTPLQRVGIFLD 127

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 283046820 408 CEGGYVSFVDVAKSSLILSYSPGTFHCAVRPFFSAVYT 445
Cdd:cd15814  128 YDAGEVSFYNVTERCHTFTFSHATFCGPVRPYFSLSYS 165

PRY/SPRY domain in tripartite motif-binding protein 39 (TRIM39) and TRIM39-like; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of pyrin, several tripartite motif-containing proteins (TRIMs), including E3 ubiquitin-protein ligase (TRIM21), RET finger protein (RFP)/tripartite motif protein 27 (TRIM27), as well as butyrophilin (Btns) and butyrophilin-like (Btnl) family members, with the exception of Btnl2. Btn and Btnl family members are novel regulators of immune responses, with many of the genes located within the MHC. They are implicated in T-cell inhibition and modulation of epithelial cell-T cell interactions. TRIM21 (also known as RO52, SSA1 or RNF81) is a major autoantigen in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjorgen's syndrome. TRIM27 (also known as Ret finger protein, RFP or RNF76) negatively regulates CD4 T-cells by ubiquitinating and inhibiting the class II phosphatidylinositol 3 kinase C2beta (PI3K-C2beta), a kinase critical for KCa3.1 channel activation. The PRY/SPRY domain of Pyrin, which is mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDP------------------WLRGRSYVATPTDLFLeclrkddhyiLITRIg 390
Cdd:cd13745   49 GAEGFTGGRHYWEVEVGDKTEWTLGVCRESvsrkgevtlspengywtvWLRDGKYEALTSPPTP----------LPVSV- 117

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 283046820 391 gehyieKPvGQVGVFLDCEGGYVSFVDVAKSSLILSYSpGTFHCAVRPFFS 441
Cdd:cd13745  118 ------RP-SRVGIFLDYEAGEVSFYNVTDRSHLFTFT-DTFSGTLRPYFY 160

PRY/SPRY domain of tripartite motif-binding protein 75 (TRIM75); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM75, also known as Gm794. TRIM75 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM75 has a single site of positive selection in its RING domain associated with E3 ubiquitin ligase activity. It has not been detectably expressed experimentally due to their constant turnover by the proteasome, and therefore not been characterized.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 333 FSRGKYYWEVDLKDYRRWTVGVCKDP---------------W---LRGRSYVAT---PTDLFLEclrkddhyilitrigg 391
Cdd:cd15829   69 FHSGRHFWEVEVGDKPEWAVGVCKDSlstkarrppsgqqgcWriqLQGGDYDAPgavPPPLLLE---------------- 132

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 283046820 392 ehyiEKPVGqVGVFLDCEGGYVSFVDVAKSSLILSYSpGTFHCAVRPFF 440
Cdd:cd15829  133 ----VKPRG-IGVFLDYELGEISFYNMPEKSHIHTFT-DTFSGPLRPYF 175

PRY/SPRY domain of tripartite motif-binding protein 17 (TRIM17), also known as testis RING finger protein (terf); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM17, also known as RING finger protein 16 (RNF16) or testis RING finger protein (terf). TRIM17 domain is composed of RING/B-box/coiled-coil core and also known as RBCC protein, expressed almost exclusively in the testis. It exhibits E3 ligase activity, causing protein degradation of ZW10 interacting protein (ZWINT), a known component of the kinetochore complex required for the mitotic spindle checkpoint, and negatively regulates proliferation of breast cancer cells. TRIM17 undergoes ubiquitination in COS7 fibroblast-like cells but is inhibited and stabilized by TRIM44.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEV--DLKDYRRWTVGVCKDPWLRGRSYVATPTDLF-LECLRKDDHYILITRIGGEHYIEKPVGQVGVF 405
Cdd:cd15812   46 GQETFSSGRHYWEVgmNLTGDALWALGVCRDNVSRKDRVPKSPENGFwVVQLSKGKKYLSAMSALTPVTLTEPPSHMGIF 125

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 283046820 406 LDCEGGYVSFVDVAKSSLILSYSPGTFHCAVRPFF 440
Cdd:cd15812  126 LDFEAGEVSFYSVNDGSHLHTYSQAAFPGPLQPFF 160

PRY/SPRY domain of tripartite motif-binding protein 60 (TRIM60) also known as RING finger protein 33 (RNF33); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM60, which is also known as RING finger protein 33 (RNF33) or 129 (RNF129). TRIM60 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. Based on its expression profile, RNF33 likely plays an important role in the spermatogenesis process, the development of the pre-implantation embryo, and in testicular functions; Rnf33 is temporally transcribed in the unfertilized egg and the pre-implantation embryo, and is permanently silenced before the blastocyst stage. Mice experiments have shown that RNF33 associates with the cytoplasmic motor proteins, kinesin-2 family members 3A (KIF3A) and 3B (KIF3B), suggesting possible contribution to cargo movement along the microtubule in the expressed sites.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLFLeCLRKDDHYILITrIGGEHYIEKPV---GQVGVF 405
Cdd:cd15828   56 GSEGFHSGRQYWEVEVGDKPEWTLGVCQDCLPRNWSNQPSVQDGLW-AIGRYSESNYVA-LGPKKIQLLPKvrpSKIGIF 133

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 283046820 406 LDCEGGYVSFVDVAKSSLILSYSpGTFHCAVRPFFS 441
Cdd:cd15828  134 LDYELGEVSFYNMNDRSLLYTFS-DSFTGTLWPYFY 168

PRY/SPRY domain in tripartite motif-containing proteins 1, 9, 18, 36, 46, 67,76 (TRIM1, TRIM9, TRIM18, TRIM36, TRIM46, TRIM67, TRIM76); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several Class I TRIM proteins, including TRIM1, TRIM9, TRIM18, TRIM36, TRIM46, TRIM67 and TRIM76. TRIM1 (also known as MID2) and its close homolog, TRIM18 (also known as MID1), both contain a B30.2-like domain at their C-terminus and a single fibronectin type III (FN3) motif between it and their N-terminal RBCC domain. Their coiled-coil motifs mediate both homo- and heterodimerization, a prerequisite for association of the rapamycin-sensitive PP2A regulatory subunit Alpha 4 with microtubules. Mutations in TRIM18 have shown to cause Opitz syndrome, a disorder causing congenital anomalies such as cleft lip and palate as well as heart defects. TRIM9 is expressed mainly in the cerebral cortex, and functions as an E3 ubiquitin ligase. Its immunoreactivity is severely decreased in affected brain areas in Parkinson's disease and dementia with Lewy bodies, possibly playing an important role in the regulation of neuronal function and participating in pathological process of Lewy body disease through its ligase. TRIM36 interacts with centromere protein-H, one of the kinetochore proteins and possibly associates with chromosome segregation; an excess of TRIM36 may cause chromosomal instability. TRIM46 has not yet been characterized. TRIM67 negatively regulates Ras activity via degradation of 80K-H, leading to neural differentiation, including neuritogenesis. TRIM76 (also known as cardiomyopathy-associated protein 5 or CMYA5) is a muscle-specific member of the TRIM superfamily, but lacks the RING domain. It is possibly involved in protein kinase A signaling as well as vesicular trafficking. It has also been implicated in Duchenne muscular dystrophy and cardiac disease. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVC-----KDPWLRGRSYVatptdlflECLRKDDHYILiTRIGGEHYIEKPVG--- 400
Cdd:cd13734   47 GDVAISSGRHYWEVSVSRSTSYRVGVAyksapRDEDLGKNSTS--------WCLSRDNNRYT-ARHDGKVVDLRVTGhpa 117

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 283046820 401 QVGVFLDCEGGYVSFVDVAKSSLILsyspgTFHCA----VRPFFS 441
Cdd:cd13734  118 RIGVLLDYDNGTLSFYDAESKQHLY-----TFHVDfegpVCPAFA 157

PRY/SPRY domain of tripartite motif-binding protein 11 (TRIM11), also known as RING finger protein 92 (RNF92); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM11, also known as RING finger protein 92 (RNF92) or BIA1. TRIM11 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It localizes to the nucleus and the cytoplasm; it is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 increases expression of dopamine beta-hydroxylase gene by interacting with the homeodomain transcription factor, PHOX2B, via the B30.2/SPRY domain, thus playing a potential role in the specification of noradrenergic (NA) neuron phenotype. It has also been shown that TRIM11 plays a critical role in the clearance of mutant PHOX2B, which causes congenital central hypoventilation syndrome, via the proteasome. TRIM11 binds a key component of the activator-mediated cofactor complex (ARC105), and destabilizes it, through the ubiquitin-proteasome system; ARC105 mediates chromatin-directed transcription activation and is a key regulatory factor for transforming growth factor beta (TGFbeta) signaling.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLFleclrkddhYILITrIGGEHYIEK--------PVG 400
Cdd:cd15811   46 GRERFTSGRHYWEVEVGDRTSWALGVCKENVNRKEKGELSAGNGF---------WILVF-LGNYYSSERrtfaplrdPPR 115

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 283046820 401 QVGVFLDCEGGYVSFVDVAKSSLILSYSPGTFHCAVRPFFS 441
Cdd:cd15811  116 RVGIFLDYEAGHLSFYSATDGSLLFIFPETPFSGTLRPLFS 156

B-box-type 2 zinc finger found in tripartite motif-containing proteins TRIM43, TRIM48, TRIM49, TRIM51, TRIM64, TRIM77 and similar proteins; The family includes a group of closely related uncharacterized tripartite motif-containing proteins, TRIM43, TRIM43B, TRIM48/RNF101, TRIM49/RNF18, TRIM49B, TRIM49C/TRIM49L2, TRIM49D/TRIM49L, TRIM51/SPRYD5, TRIM64, TRIM64B, TRIM64C, and TRIM77, whose biological functions remain unclear. TRIM49, also known as testis-specific RING-finger protein, has moderate similarity with SS-A/Ro52 antigen, suggesting it may be one of target proteins of autoantibodies in the sera of patients with these autoimmune disorders. All family members (except for TRIM51) belong 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, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM51 belongs to unclassified TRIM (tripartite motif) family of proteins that do not have RING fingers. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 283046820  87 NSEEHKCVTHKAKKMIFCDKSKILLCHLCSDSQEHSGHTHCSIDVAVQEKMEE 139
Cdd:cd19783    1 SSEEQICGTHRETKKLFCEADKSLLCLLCSSSQEHRAHRHYPIEWAAEEHREK 53

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM43, TRIM48, TRIM49, TRIM51, TRIM64 and similar proteins; The family includes a group of closely related uncharacterized tripartite motif-containing proteins, TRIM43, TRIM43B, TRIM48/RNF101, TRIM49/RNF18, TRIM49B, TRIM49C/TRIM49L2, TRIM49D/TRIM49L, TRIM51/SPRYD5, TRIM64, TRIM64B, and TRIM64C, whose biological function remain unclear. TRIM49, also known as testis-specific RING-finger protein, has moderate similarity with SS-A/Ro52 antigen, suggesting it may be one of the target proteins of autoantibodies in the sera of patients with these autoimmune disorders. All family members belong to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. In RBCC region, they all have a C3HC4-type RING-HC finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 283046820  14 LTCSICQGIFMNPVYLKCGHKFCEACLLLFQEDIKFPAYCPMCMQPFNQ 62
Cdd:cd16603    5 LTCPICMNYFIDPVTIDCGHSFCRPCLYLNWQDIPFLAQCPECRKTTEQ 53

PRY/SPRY domain in tripartite motif-binding protein 7 (TRIM7)-like, including TRIM7, TRIM10, TRIM15, TRIM26, TRIM39, TRIM41; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several tripartite motif-containing (TRIM) proteins, including TRIM7 (also referred to as glycogenin-interacting protein, RING finger protein 90 or RNF90), TRIM10, TRIM15, TRIM26, TRIM39 and TRIM41. TRIM7 or GNIP interacts with glycogenin and stimulates its self-glucosylating activity via its SPRY domain. TRIM10 (also known as hematopoietic RING finger 1 (HERF1) or TRIM10/HERF1) plays a key role in definitive erythroid development; downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival. Antiviral activity of TRIM15 is dependent on the ability of its B-box to interact with the MLV Gag precursor protein; downregulation of TRIM15, along with TRIM11, enhances virus release suggesting that these proteins contribute to the endogenous restriction of retroviruses in cells. Tripartite motif-containing 26 (TRIM26) function is as yet unknown; however, since it is localized in the human histocompatibility complex (MHC) class I region, TRIM26 may play a role in immune response although studies show no association between TRIM26 polymorphisms and the risk of aspirin-exacerbated respiratory disease. TRIM39 is a MOAP-1 (Modulator of Apoptosis)-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process. TRIM41 (also known as RING finger-interacting protein with C kinase or RINCK) functions as an E3 ligase that catalyzes the ubiquitin-mediated degradation of protein kinase C.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCK-----------DP----W---LRGRSYVA-----TPTDLfLECLRKddhyil 385
Cdd:cd12888   46 GCEGFTSGRHYWEVEVGDGGGWAVGVAResvrrkgeisfSPeegiWavgQWGGQYWAltspeTPLPL-SEVPRR------ 118

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 283046820 386 itriggehyiekpvgqVGVFLDCEGGYVSFVDVAKSSLILSYSPGTF-HCAVRPFF 440
Cdd:cd12888  119 ----------------IRVYLDYEGGQVAFFDADNEAPIFTFPPASFaGERIFPWF 158

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

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 283046820  12 ETLTCSICQGIFMNPVYLKCGHKFCEACLLLFQEDIKFPAYCPMCMQPF 60
Cdd:cd16611    3 EELHCPLCLDFFRDPVMLSCGHNFCQSCITGFWELQAEDTTCPECRELC 51

PRY/SPRY domain of tripartite motif-binding protein 5, 6, 22 and 34 (TRIM5, TRIM6, TRIM22 and TRIM34); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of very close paralogs, TRIM5, TRIM6, TRIM22 and TRIM34. These domains are composed of RING/B-box/coiled-coil core and are also known as RBCC proteins. They form a locus of four closely related TRIM genes within an olfactory receptor-rich region on chromosome 11 of the human genome. Genetic analysis of this locus indicates that these four genes have evolved by gene duplication from a common ancestral gene. All genes in the TRIM6/TRIM34/TRIM5/TRIM22 locus are type I interferon inducible, with TRIM5 and TRIM22 possessing antiviral properties. TRIM5 promotes innate immune signaling by activating the TAK1 kinase complex by cooperating with the heterodimeric E2, UBC13/UEV1A. It also stimulates NFkB and AP-1 signaling, and the transcription of inflammatory cytokines and chemokines, amplifying these activities upon retroviral infection. Interaction of its PRY-SPRY or cyclophilin domains with the retroviral capsid lattice stimulates the formation of a complementary lattice by TRIM5, with greatly increased TRIM5 E3 activity, and host cell signal transduction. TRIM6 is selectively expressed in embryonic stem (ES) cells and interacts with the proto-oncogene product Myc, maintaining the pluripotency of the ES cells. TRIM6, together with E2 Ubiquitin conjugase (UbE2K) and K48-linked poly-Ub chains, is critical for the IkappaB kinase epsilon (IKKepsilon) branch of type I interferon (IFN-I) signaling pathway and subsequent establishment of a protective antiviral response. TRIM22 plays an integral role in the host innate immune response to viruses; it has been shown to inhibit the replication of a number of viruses, including HIV-1, hepatitis B, and influenza A. Altered TRIM22 expression has also been associated with multiple sclerosis, cancer, and autoimmune disease. While the PRY-SPRY domain of TRIM5a provides specificity and the capsid recognition motif to retroviral restriction, TRIM34 binds HIV-1 capsid but does not restrict HIV-1 infection.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKdpwlrGRSYVATPTDLFLECLRKDDH--------YILITRIGGEHY------ 394
Cdd:cd15810   45 GSQYFSSGKHYWEVDVSKKSAWILGVCS-----HKRSDAMTKSNANQINHQNVYsryqpqygYWVIGLQNESEYnafeds 119

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 283046820 395 -----------IEKPVGQVGVFLDCEGGYVSFVDVAK-SSLILSYSPGTFHCAVRPFF 440
Cdd:cd15810  120 ssfnphvltlsVTVPPHRVGVFLDYEAGTVSFFNVTNhGSLIYKFSKCCFSTTVCPYF 177

RING finger, HC subclass, found in tripartite motif-containing protein 10 (TRIM10) and similar proteins; TRIM10, also known as B30-RING finger protein (RFB30), RING finger protein 9 (RNF9), or hematopoietic RING finger 1 (HERF1), is a novel hematopoiesis-specific RING finger protein required for terminal differentiation of erythroid cells. TRIM10 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 283046820  12 ETLTCSICQGIFMNPVYLKCGHKFCEACLLLFQE----DIKFPAYCPMCMQPF 60
Cdd:cd16593    4 DEVNCPICQGTLREPVTIDCGHNFCRACLTRYCEipgpDLEEPPTCPLCKEPF 56

PRY/SPRY domain in tripartite motif-containing protein 22 (TRIM22), also known as RING finger protein 94 (RNF94) or Stimulated trans-acting factor of 50 kDa (STAF50); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM22, also known as RING finger protein 94 (RNF94) or STAF50 (Stimulated trans-acting factor of 50 kDa). TRIM6 domain is composed of RING/B-box/coiled-coil core and also known as RBCC protein. TRIM22 is an interferon-induced protein, predominantly expressed in peripheral blood leukocytes, in lymphoid tissue such as spleen and thymus, and in the ovary.TRIM22 plays an integral role in the host innate immune response to viruses; it has been shown to inhibit the replication of a number of viruses, including HIV-1, hepatitis B, and influenza A. TRIM22 inhibits influenza A virus (IAV) infection by targeting the viral nucleoprotein for degradation; it represents a novel restriction factor up-regulated upon IAV infection that curtails its replicative capacity in epithelial cells. Altered TRIM22 expression has also been associated with multiple sclerosis, cancer, and autoimmune disease. A large number of high-risk non-synonymous (ns)SNPs have been identified in the highly polymorphic TRIM22 gene, most of which are located in the SPRY domain and could possibly alter critical regions of the SPRY structural and functional residues, including several sites that undergo post-translational modification. TRIM22 is a direct p53 target gene and inhibits the clonogenic growth of leukemic cells. Its expression in Wilms tumors is negatively associated with disease relapse. It is greatly under-expressed in breast cancer cells as compared to non-malignant cell lines; p53 dysfunction may be one of the mechanisms for its down-regulation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 328 WGKKSFSRGKYYWEVDLKDYRRWTVGV-CKDPWLRGRS---YVATPT----DLFLECLRKDDHYILITRIGGEH------ 393
Cdd:cd15824   47 LGCQYFSSGKYYWEVDVSGKIAWILGVySKRNNLNKRKssgFAFDPNvnhpNVYSRYRPQNGYWVIGLQNESEYnafeds 126

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 283046820 394 ----------YIEKPVGQVGVFLDCEGGYVSFVDVAK-SSLILSYSPGTFHCAVRPFFS 441
Cdd:cd15824  127 sssdpkvltlSMAVPPHRVGVFLDYEAGTVSFFNVTNhGSLIYKFSKCCFSQPVYPYFN 185

zinc-binding protein A33-like; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM69 and TRIM proteins NF7 and bloodthirsty (bty). TRIM69 is a novel testis E3 ubiquitin ligase that may function to ubiquitinate its particular substrates during spermatogenesis. In humans, TRIM69 localizes in the cytoplasm and nucleus, and requires an intact RING finger domain to function. TRIM protein NF7, which also contains a chromodomain (CHD) at the N-terminus and an RFP (Ret finger protein)-like domain at the C-terminus, is required for its association with transcriptional units of RNA polymerase II which is mediated by a trimeric B box. In Xenopus oocyte, xNF7 has been identified as a nuclear microtubule-associated protein (MAP) whose microtubule-bundling activity, but not E3-ligase activity, contributes to microtubule organization and spindle integrity. Bloodthirsty (bty) is a novel gene identified in zebrafish and has been shown to likely play a role in in regulation of the terminal steps of erythropoiesis.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDPWLRGRSYVATPTDLFLEC-LRKDDHYILITRIGGEHYIEKPVGQVGVFLD 407
Cdd:cd12905   50 ASQGFQSGRHYWEVWVGSKTKWDLGVASESVDRQARVKLCPENGYWTLrLRNGDEYWAGTQPWTRLRVTSRPQRIGVFLD 129

                         90       100       110
                 ....*....|....*....|....*....|....
gi 283046820 408 CEGGYVSFVDVAKSSLILSYSPGTFHcAVRPFFS 441
Cdd:cd12905  130 CEERKVSFYNADDMSLLYSFHQGPRG-KVFPFFS 162

RING finger, HC subclass, found in tripartite motif-containing protein 39 (TRIM39) and similar proteins; TRIM39, also known as RING finger protein 23 (RNF23) or testis-abundant finger protein, is an E3 ubiquitin-protein ligase that plays a role in controlling DNA damage-induced apoptosis through inhibition of the anaphase promoting complex (APC/C), a multiprotein ubiquitin ligase that controls multiple cell cycle regulators, including cyclins, geminin, and others. TRIM39 also functions as a regulator of several key processes in the proliferative cycle. It directly regulates p53 stability. It modulates cell cycle progression and DNA damage responses via stabilizing p21. Moreover, TRIM39 negatively regulates the nuclear factor kappaB (NFkappaB)-mediated signaling pathway through stabilization of Cactin, an inhibitor of NFkappaB- and Toll-like receptor (TLR)-mediated transcription, which is induced by inflammatory stimulants such as tumor necrosis factor alpha. Furthermore, TRIM39 is a MOAP-1-binding protein that can promote apoptosis signaling through stabilization of MOAP-1 via the inhibition of its poly-ubiquitination process. TRIM39 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|.
gi 283046820  16 CSICQGIFMNPVYLKCGHKFCEACLLLFQEDIKFPAYCPMC 56
Cdd:cd16601    4 CSLCKEYLKDPVIIECGHNFCRACITRFWEELDGDFPCPQC 44

PRY/SPRY domain in tripartite motif-binding protein 4 (TRIM4), also known as RING finger protein 87 (RNF87); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM4 which is also known as RING finger protein 87 (RNF87). TRIM4 domain is composed of RING/B-box/coiled-coil core and also known as RBCC protein. It is a positive regulator of RIG-I-mediated interferon (IFN) induction. It regulates virus-induced IFN induction and cellular antiviral innate immunity by targeting RIG-I for K63-linked poly-ubiquitination. Over-expression of TRIM4 enhances virus-triggered activation of transcription factors IRF3 and NF-kappaB, as well as IFN-beta induction. Expression of TRIM4 differs significantly in Huntington's Disease (HD) neural cells when compared with wild-type controls, possibly impacting down-regulation of the Huntingtin (HTT) gene, which is involved in the regulation of diverse cellular activities that are impaired in Huntington's Disease (HD) cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCKDP--WLRGRSYVATPTDLFLECLRKDDHYILITRIGGEHYIEKPVGQVGVFL 406
Cdd:cd15809   68 GKNVFTSGKHYWEVENRDSLEIAVGVCREDvmGITDGSEMSPHVGIWAICWSSAGYRPLTSSPVSPTKQEPALHRVGVFL 147

                         90       100       110
                 ....*....|....*....|....*....|....
gi 283046820 407 DCEGGYVSFVDVAKSSLILSYSPGTFHCaVRPFF 440
Cdd:cd15809  148 DHGAGEVSFYSAVDGVHLHTFSCPLVSR-LRPFF 180

RING finger, HC subclass, found in RING finger protein 39 (RNF39) and similar proteins; RNF39, also called protein HZFw, may play a role in prolonged long term-potentiation (LTP) maintenance. It is involved in the etiology of Behcet's disease (BD). It may also be involved in HIV-1 replication. RNF39 acts as an E3 ubiquitin ligase that inhibits retinoic acid-inducible gene-I (RIG-I)-like receptor (RLR) pathways by mediating K48-linked ubiquitination and proteasomal degradation of DDX3X (DEAD-box RNA helicase 3, X-linked). RNF39 contains a typical C3HC4-type RING-HC finger.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 283046820  10 QEETlTCSICQGIFMNPVYLKCGHKFCEACLLLF--QEDIKF----PAYCPMCMQPF 60
Cdd:cd16592    2 QEET-TCPICLGYFKDPVILDCEHSFCRACIARHwgQEAMEGngaeGVFCPQCGEPC 57

RING finger, HC subclass, found in RING finger proteins RNF113A, RNF113B, and similar proteins; RNF113A, also known as zinc finger protein 183 (ZNF183), is an E3 ubiquitin-protein ligase that physically interacts with the E2 protein, UBE2U. A nonsense mutation in RNF113A is associated with an X-linked trichothiodystrophy (TTD). Its yeast ortholog Cwc24p is predicted to have a spliceosome function and acts in a complex with Cef1p to participate in pre-U3 snoRNA splicing, indirectly affecting pre-rRNA processing. It is also important for the U2 snRNP binding to primary transcripts and co-migrates with spliceosomes. Moreover, the ortholog of RNF113A in fruit flies may also act as a spliceosome and is hypothesized to be involved in splicing, namely within the central nervous system. The ortholog in Caenorhabditis elegans is involved in DNA repair of inter-strand crosslinks. RNF113B, also known as zinc finger protein 183-like 1, shows high sequence similarity with RNF113A. Both RNF113A and RNF113B contain a CCCH-type zinc finger, which is commonly found in RNA-binding proteins involved in splicing, and a C3HC4-type RING-HC finger, which is frequently found in E3 ubiquitin ligases.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 283046820  15 TCSICQGIFMNPVYLKCGHKFCEACLLL-FQEDIKfpayCPMCMQPFN 61
Cdd:cd16539    7 ACFICRKPFKNPVVTKCGHYFCEKCALKhYRKSKK----CFVCGKQTN 50

PRY/SPRY domain in tripartite motif-binding protein 6 (TRIM6), also known as RING finger protein 89 (RNF89); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM6, also known as RING finger protein 89 (RNF89). TRIM6 domain is composed of RING/B-box/coiled-coil core and also known as RBCC protein. It is selectively expressed in embryonic stem (ES) cells and interacts with the proto-oncogene product Myc, maintaining the pluripotency of the ES cells. TRIM6, together with E2 Ubiquitin conjugase (UbE2K) and K48-linked poly-Ub chains, is critical for the IkappaB kinase epsilon (IKKepsilon) branch of type I interferon (IFN-I) signaling pathway and subsequent establishment of a protective antiviral response.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCkdpwlrgrSYVATPTDLFLECLRKDDHYiliTR---------IGGEH------ 393
Cdd:cd15823   48 GSQHFSSGKHYWEVDVTKKTAWILGVC--------SHSLGPTFSFNQYAQNHNAY---SRyqpqsgywvIGLQHnheyra 116

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 283046820 394 ----------YIEKPVGQVGVFLDCEGGYVSFVDVAKSSL-ILSYSPGTFHCAVRPFFSAV 443
Cdd:cd15823  117 yedsstslllSMTVPPRRVGVFLDYEAGTVSFYNVTNHGFpIYTFSKYYFPTTLCPYFNPC 177

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 283046820  12 ETLTCSICQGIFMNPVYL-KCGHKFCEACLLLFQEdiKFPAYCPMCMQPFNQEY 64
Cdd:cd16544    1 AELTCPVCQEVLKDPVELpPCRHIFCKACILLALR--SSGARCPLCRGPVGKTE 52

RING finger, HC subclass, found in tripartite motif-containing protein 8 (TRIM8) and similar proteins; TRIM8, also known as glioblastoma-expressed RING finger protein (GERP) or RING finger protein 27 (RNF27), is a probable E3 ubiquitin-protein ligase that may promote proteasomal degradation of suppressor of cytokine signaling 1 (SOCS1) and further regulate interferon-gamma signaling. It functions as a new p53 modulator that stabilizes p53 impairing its association with MDM2 and inducing the reduction of cell proliferation. TRIM8 deficit dramatically impairs p53 stabilization and activation in response to chemotherapeutic drugs. TRIM8 also modulates tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta)-triggered nuclear factor-kappaB (NF- kappa B) activation by targeting transforming growth factor beta (TGFbeta) activated kinase 1 (TAK1) for K63-linked polyubiquitination. Moreover, TRIM8 modulates translocation of phosphorylated STAT3 into the nucleus through interaction with Hsp90beta and consequently regulates transcription of Nanog in embryonic stem cells. It also interacts with protein inhibitor of activated STAT3 (PIAS3), which inhibits IL-6-dependent activation of STAT3. TRIM8 belongs to the C-V subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil domain, as well as an uncharacterized region positioned C-terminal to the RBCC domain. The coiled coil domain is required for homodimerization and the region immediately C-terminal to the RING motif is sufficient to mediate the interaction with SOCS1.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 283046820  11 EETLTCSICQGIFMNPVYLKCGHKFCEACLLLFQEDIKFPAYCPMCMQPFNQE 63
Cdd:cd16580    9 EEELICPICLHVFVEPVQLPCKHNFCRGCIGEAWAKDAGLVRCPECNQAYNQK 61

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM5, TRIM6, TRIM22, TRIM34 and similar proteins; TRIM5, TRIM6, TRIM22, and TRIM34, four closely related tripartite motif-containing proteins, belong to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. TRIM5, also known as RING finger protein 88 (RNF88), is a capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. Its retroviral restriction activity correlates with the ability to activate TAK1-dependent innate immune signaling. TRIM5 also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Moreover, TRIM5 plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2. It also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction. TRIM6, also known as RING finger protein 89 (RNF89), is an E3-ubiquitin ligase that cooperates with the E2-ubiquitin conjugase UbE2K to catalyze the synthesis of unanchored K48-linked polyubiquitin chains, and further stimulates the interferon-I kappa B kinase epsilon (IKKepsilon) kinase-mediated antiviral response. It also regulates the transcriptional activity of Myc during the maintenance of embryonic stem (ES) cell pluripotency, and may act as a novel regulator for Myc-mediated transcription in ES cells. TRIM22, also known as 50 kDa-stimulated trans-acting factor (Staf-50) or RING finger protein 94 (RNF94), is an E3 ubiquitin-protein ligase that plays an integral role in the host innate immune response to viruses. It has been shown to inhibit the replication of a number of viruses, including HIV-1, hepatitis B, and influenza A. TRIM22 acts as a suppressor of basal HIV-1 long terminal repeat (LTR)-driven transcription by preventing the transcription factor specificity protein 1 (Sp1) binding to the HIV-1 promoter. It also controls FoxO4 activity and cell survival by directing Toll-like receptor 3 (TLR3)-stimulated cells toward type I interferon (IFN) type I gene induction or apoptosis. Moreover, TRIM22 can activate the noncanonical nuclear factor-kappaB (NF-kappaB) pathway by activating I kappa B kinase alpha (IKKalpha). It also regulates nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-kappaB. TRIM34, also known as interferon-responsive finger protein 1 or RING finger protein 21 (RNF21), may function as antiviral protein that contribute to the defense against retroviral infections.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 283046820   8 DPQEETlTCSICQGIFMNPVYLKCGHKFCEACLLLFQEDIKFP---AYCPMCMQPFNQEYI 65
Cdd:cd16591    2 NIKEEV-TCPICLELLTEPLSLDCGHSFCQACITANHKESVNQegeSSCPVCRTSYQPENL 61

RING finger, HC subclass, 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 the 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 by 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 the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

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                 ....*....|....*....|....*....|....*....|....*..
gi 283046820  14 LTCSICQGIFMNPVYLKCGHKFCEACLL-LFQEDIKFPAYCPMCMQP 59
Cdd:cd16612    5 LSCPLCLKLFQSPVTTECGHTFCQDCLSrVPKEEDGGSTSCPTCQAP 51

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

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                  ....*....|....*....|....*....|....*....|..
gi 283046820   16 CSICQGIFMNPVY-LKCGHKFCEACLLLFQEDIKFpaYCPMC 56
Cdd:pfam00097   1 CPICLEEPKDPVTlLPCGHLFCSKCIRSWLESGNV--TCPLC 40

PRY/SPRY domain in tripartite motif-binding protein 5 (TRIM5), also known as RING finger protein 88 (RNF88); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM5 which is also known as RING finger protein 88 (RNF88) or TRIM5alpha (TRIM5a), an antiretroviral restriction factor and a retrovirus capsid sensor in immune signaling. TRIM5 domain is composed of RING/B-box/coiled-coil core and also known as RBCC protein. It blocks retrovirus infection soon after the virion core enters the cell cytoplasm by recognizing the capsid protein lattice that encases the viral genomic RNA; the SPRY domain provides the capsid recognition motif that dictates specificity to retroviral restriction. TRIM5a, an E3 ubiquitin ligase, promotes innate immune signaling by activating the TAK1 kinase complex by cooperating with the heterodimeric E2, UBC13/UEV1A. It also stimulates NFkB and AP-1 signaling, and the transcription of inflammatory cytokines and chemokines, and amplifies these activities upon retroviral infection. Interaction of its PRY-SPRY or cyclophilin domains with the retroviral capsid lattice stimulates the formation of a complementary lattice by TRIM5, with greatly increased TRIM5 E3 activity, and host cell signal transduction.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 283046820 329 GKKSFSRGKYYWEVDLKDYRRWTVGVCkdpwlrGRSYVATPTDLFLECLRKddHYILITR---------IGGEHYIEK-- 397
Cdd:cd15822   55 GSPSITSGKHYWEVDVSKKRAWILGVC------GGKYPNSTLKDFNKQGKN--NQKQCSNyqpkygywvIGLQNKSEYna 126

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 283046820 398 ------------------PVGQVGVFLDCEGGYVSFVDVAKS-SLILSYSPGTFHCAVRPFFS 441
Cdd:cd15822  127 fedssssdpliltlsltvPPCRVGVFLDYEAGTVSFFNVTNHgFLIYKFSSCSFSQEVFPYFN 189