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 153791360  93 FREDVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDP-RL---ACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPAD 168
Cdd:cd15821    2 FQVDMTLDVDTANNYLIISEDLRSVRCGCFRQNRKELAeRFddaLCVLGSPRFTSGRHYWEVDVGTSTEWDLGVCRESVN 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 169 RKSN-DLFPEHGFWI-SMKAGAIH-ANT-HLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSLELLCPF 244
Cdd:cd15821   82 RQGPiELSPEHGFWTvSLRDGSVFfASTvPLTVLWVNPRLHRVGIFLDMEMGTISFYDVSDGSHIFTFTKISAEEPLRPF 161

                        170
                 ....*....|....*...
gi 153791360 245 FCLElLGEGESGNVLTIC 262
Cdd:cd15821  162 FAPA-NPYGDDQGVLSIC 178

Ret finger protein-like (RFPL), includes RFP1, 2, 3, 4; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of RFPL protein family, which includes RFPL1, RFPL2, RFPL3 and RFPL4. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex. The human RFPL1, 2, 3 genes have a role in neocortex development. RFPL1 is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development; human RFPL1 decreases cell number through its RFPL-defining motif (RDM) and SPRY domains. The RFPL4 (also known as RFPL4A) gene encodes a putative E3 ubiquitin-protein ligase expressed in adult germ cells and interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  93 FREDVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDP-RL---ACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPAD 168
Cdd:cd15821    2 FQVDMTLDVDTANNYLIISEDLRSVRCGCFRQNRKELAeRFddaLCVLGSPRFTSGRHYWEVDVGTSTEWDLGVCRESVN 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 169 RKSN-DLFPEHGFWI-SMKAGAIH-ANT-HLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSLELLCPF 244
Cdd:cd15821   82 RQGPiELSPEHGFWTvSLRDGSVFfASTvPLTVLWVNPRLHRVGIFLDMEMGTISFYDVSDGSHIFTFTKISAEEPLRPF 161

                        170
                 ....*....|....*...
gi 153791360 245 FCLElLGEGESGNVLTIC 262
Cdd:cd15821  162 FAPA-NPYGDDQGVLSIC 178

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 153791360   143 SGQHYWEVEVGEVKSWSLGVCKEPADRKSNDLFPE-HGFW--ISMKAGAIHANTHLE-RIPASPRLRRVGIFLDADLEEI 218
Cdd:smart00449   1 SGRHYFEVEIGDGGHWRVGVATKSVPRGYFALLGEdKGSWgyDGDGGKKYHNSTGPEyGLPLQEPGDVIGCFLDLEAGTI 80

                           90       100       110
                   ....*....|....*....|....*....|..
gi 153791360   219 QFFDVDNNVLIYThdgFFSL---ELLCPFFCL 247
Cdd:smart00449  81 SFYKNGKYLHGLA---FFDVkfsGPLYPAFSL 109

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 153791360   3 KRLQAELSCPVCLDFFSCSISLSCTHVFCFDCIQRYiLENHDfraMCPLCR 53
Cdd:COG5432   20 KGLDSMLRCRICDCRISIPCETTCGHTFCSLCIRRH-LGTQP---FCPVCR 66

zinc finger of C3HC4-type, RING; This is a family of primate-specific Ret finger protein-like (RFPL) zinc-fingers of the C3HC4 type. Ret finger protein-like proteins are primate-specific target genes of Pax6, a key transcription factor for pancreas, eye and neocortex development. This domain is likely to be DNA-binding. This zinc-finger domain together with the RDM domain, pfam11002, forms a large zinc-finger structure of the RING/U-Box superfamily. RING-containing proteins are known to exert an E3 ubiquitin protein ligase activity with the zinc-finger structure being mandatory for binding to the E2 ubiquitin-conjugating enzyme.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 153791360   11 CPVCLDFFSCSISLSCTHVFCFDCIQRYILENHDFRAMCPLC 52
Cdd:pfam15227   1 CPICLDYLEKPVSIECGHSFCLSCINSLQKEPDGESLLCPQC 42

N1R/p28-like protein; Provisional

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 153791360  11 CPVCLD----------FFScsISLSCTHVFCFDCIQRYILENHdfraMCPLCR 53
Cdd:PHA02929 177 CAICMEkvydkeiknmYFG--ILSNCNHVFCIECIDIWKKEKN----TCPVCR 223

Ret finger protein-like (RFPL), includes RFP1, 2, 3, 4; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of RFPL protein family, which includes RFPL1, RFPL2, RFPL3 and RFPL4. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex. The human RFPL1, 2, 3 genes have a role in neocortex development. RFPL1 is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development; human RFPL1 decreases cell number through its RFPL-defining motif (RDM) and SPRY domains. The RFPL4 (also known as RFPL4A) gene encodes a putative E3 ubiquitin-protein ligase expressed in adult germ cells and interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  93 FREDVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDP-RL---ACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPAD 168
Cdd:cd15821    2 FQVDMTLDVDTANNYLIISEDLRSVRCGCFRQNRKELAeRFddaLCVLGSPRFTSGRHYWEVDVGTSTEWDLGVCRESVN 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 169 RKSN-DLFPEHGFWI-SMKAGAIH-ANT-HLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSLELLCPF 244
Cdd:cd15821   82 RQGPiELSPEHGFWTvSLRDGSVFfASTvPLTVLWVNPRLHRVGIFLDMEMGTISFYDVSDGSHIFTFTKISAEEPLRPF 161

                        170
                 ....*....|....*...
gi 153791360 245 FCLElLGEGESGNVLTIC 262
Cdd:cd15821  162 FAPA-NPYGDDQGVLSIC 178

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 153791360  93 FREDVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPR----LACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPAD 168
Cdd:cd13745    1 FAVDVTLDPDTAHPNLVLSEDRKSVRHGDTRQDLPDNPErfdtYPCVLGAEGFTGGRHYWEVEVGDKTEWTLGVCRESVS 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 169 RKSNDLF-PEHGFW-ISMKAGAIHANT-HLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSlELLCPFF 245
Cdd:cd13745   81 RKGEVTLsPENGYWtVWLRDGKYEALTsPPTPLPVSVRPSRVGIFLDYEAGEVSFYNVTDRSHLFTFTDTFS-GTLRPYF 159

                        170
                 ....*....|....*...
gi 153791360 246 CLELLGEGESGNVLTICP 263
Cdd:cd13745  160 YPGLNAGGKNAAPLIICP 177

butyrophilin subfamily member A1 and A2 (BTN1A and BTN2A); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of butyrophilin family 1A and 2A (BTN1A and BTN2A). BTNs belong to receptor glycoproteins of immunoglobulin (Ig) superfamily, characterized by the presence of extracellular Ig-like domains (IgV and/or IgC). BTN1A plays a role in the secretion, formation and stabilization of milk fat globules. The B30.2 domain of BTN1A1 binds the enzyme xanthine oxidoreductase (XOR) in order to participate in milk fat globule secretion; this interaction may lead to the production of reactive oxygen species, which have immunomodulatory and antimicrobial functions. Duplication events have led to three paralogs of BTN2A in primates: BTN2A1, BTN2A2, and BTN2A3. In humans, only BTN2A1 has been functionally characterized; it has been detected on epithelial cells and leukocytes, and identified as a novel ligand of dendritic cell-specific ICAM-3 grabbing nonintegrin (DCSIGN), a C-type lectin receptor that acts as an internalization receptor for HIV-1, HCV, and other pathogens. BTN2A2 mRNA has been shown to be expressed in circulating human immune cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPR----LACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRKS 171
Cdd:cd15819    3 NVTLDPDTAHPALILSEDGRSVTWGETRQDLPENPErfdsLPCVLGQEGFTSGRHYWEVEVGDRTSWDLGVCRDNVMRKG 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 172 ND-LFPEHGFW-ISMKAGAIHANTHLE-RIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYT--HDGFFSleLLCPFFC 246
Cdd:cd15819   83 RVtLSPENGFWaIRLYGNEYWALTSPEtPLTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTfpQTAFSG--PLRPFFR 160

                        170
                 ....*....|....*.
gi 153791360 247 lelLGEGESGNvLTIC 262
Cdd:cd15819  161 ---LWSSDSGP-LTIC 172

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 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPR----LACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRKS 171
Cdd:cd15814    3 DVTLDPDTAYPSLILSDNLRQVRYSYLQQDLPDNPErfnlFPCVLGSPCFIAGRHYWEVEVGDKAKWTIGVCEDSVCRKG 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 172 N-DLFPEHGFW-ISMKAGAIH--ANTHLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYThdgfFSLELLC----P 243
Cdd:cd15814   83 GvTSAPQNGFWaVSLWYGKEYwaLTSPMTALPLRTPLQRVGIFLDYDAGEVSFYNVTERCHTFT----FSHATFCgpvrP 158

                        170       180
                 ....*....|....*....|
gi 153791360 244 FFCLELLGeGESGNVLTICP 263
Cdd:cd15814  159 YFSLSYSG-GKSAAPLIICP 177

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 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPRL----ACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRK- 170
Cdd:cd15811    1 DVTLDPDTANPELVLSEDRRSVRRGDLRQALPDSPERfdpgPCVLGRERFTSGRHYWEVEVGDRTSWALGVCKENVNRKe 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 153791360 171 SNDLFPEHGFWISMKAGAIHANTHLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYT 231
Cdd:cd15811   81 KGELSAGNGFWILVFLGNYYSSERRTFAPLRDPPRRVGIFLDYEAGHLSFYSATDGSLLFI 141

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 153791360  91 RHFREDVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPR----LACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEP 166
Cdd:cd15828    6 KRFQVDVTLDPETAHPQLTVSEDRKSVLYGEMKQNVCYNPRrfylCPAVLGSEGFHSGRQYWEVEVGDKPEWTLGVCQDC 85

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 167 ADRK-SNDLFPEHGFWismkagAIHANTH-------LERIPASPRLR--RVGIFLDADLEEIQFFDVDNNVLIYTHDGFF 236
Cdd:cd15828   86 LPRNwSNQPSVQDGLW------AIGRYSEsnyvalgPKKIQLLPKVRpsKIGIFLDYELGEVSFYNMNDRSLLYTFSDSF 159

                        170
                 ....*....|
gi 153791360 237 SlELLCPFFC 246
Cdd:cd15828  160 T-GTLWPYFY 168

PRY/SPRY domain in tripartite motif-binding protein 58 (TRIM58), also known as BIA2; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM58, also known as BIA2. TRIM58 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins.It is implicated by genome-wide association studies (GWAS) to regulate erythrocyte traits, including cell size and number. Trim58 facilitates erythroblast enucleation by inducing proteolytic degradation of the microtubule motor dynein.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPR----LACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRKS 171
Cdd:cd15816    1 DVKLDPATAHPSLLLTADLRSVQDGELWRDVPGNPErfdtWPCVLGLQSFSSGRHYWEVAVGEKAEWGLGVCQDSAPRKG 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 172 NDL-FPEHGFWismKAGAIHANTHLerIPASP--------RLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSlELLC 242
Cdd:cd15816   81 ETTpSPENGVW---AVWLLKGNEYM--VLASPsvpllqlrRPRRVGVFLDYEAGEISFYNVTAGSHIYTFRQLFS-GILR 154

                 ...
gi 153791360 243 PFF 245
Cdd:cd15816  155 PYF 157

PRY/SPRY domain in tripartite motif-containing protein 35 (TRIM35); This PRY/SPRY domain is found at the C-terminus of the overall domain architecture of tripartite motif 35, TRIM35 (also known as hemopoietic lineage switch protein), which includes a RING finger domain (RING) and a B-box motif (BBOX). TRIM35 may play a role as a tumor suppressor and is implicated in the cell death mechanism.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  97 VTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDP----RLACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRK-S 171
Cdd:cd12893    2 VTLDPNTAHPWLSLSEDLTSVRYSSEKQQLPDNPerfdPYPCVLGSEGFTSGKHSWDVEVGDNTSWMLGVAKESVQRKgK 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 172 NDLFPEHGFWISM----KAGAIHANTHLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYT-HDGFFslELLCPFFC 246
Cdd:cd12893   82 FTLSPESGFWTIGfsegKYSARTSPEPRTPLRVKQKPQRIRVQLDWDRGKVSFSDPDTNTHIHTfTHTFT--ERVFPYFY 159

                        170
                 ....*....|....*..
gi 153791360 247 LELLGEGesgnvLTICP 263
Cdd:cd12893  160 TGCKSEP-----LRILP 171

PRY/SPRY domain of tripartite motif-binding protein 60 and 75 (TRIM60 and TRIM75); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM60 and TRIM75, both composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM60 domain is also known as RING finger protein 33 (RNF33) or 129 (RNF129). 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. TRIM75, also known as Gm794, 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 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPR----LACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRKS 171
Cdd:cd15817    1 DLILDPETAHPNLIVSEDRKAVRYRRMKPNCPYDPRrftvYPAVLGSEGFDSGRHFWEVEVGGKGEWILGVCKDSLPRNA 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 172 NDL-FPEHGFW-ISMKAGAIHA-NTHLERIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSlELLCPFFCLe 248
Cdd:cd15817   81 QDPpSPLGGCWqIGRYMSGYVAsGPKTTQLLPVVKPSRIGIFLDYELGEVSFYNMNDRSHLYTFTDTFT-GKLIPYFYV- 158

                        170
                 ....*....|....
gi 153791360 249 llgeGESGNVLTIC 262
Cdd:cd15817  159 ----GPDSEPLTIC 168

PRY/SPRY domain in tripartite motif-binding protein 15 (TRIM15); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of tripartite motif-containing protein 15 (TRIM15), also referred to as RING finger protein 93 (RNF93) or Zinc finger protein B7 or 178 (ZNFB7 or ZNF178). TRIM15 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. The PRY and SPRY/B30.2 domains can function as immune defense components and in pathogen sensing. TRIM15 has been shown to regulate inflammatory and innate immune signaling, in addition to displaying antiviral activities. Down-regulation of TRIM15, as well as TRIM11, enhances virus release, suggesting that these proteins contribute to the endogenous restriction of retroviruses in cells. TRIM15 is also a regulatory component of focal adhesion turnover and cell migration.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  97 VTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDP-RLAC---VLGTPCFSSGQHYWEVEV--GEVKSWSLGVCKEPADRK 170
Cdd:cd15826    2 VTLDPQTASGSLVLSEDRKSVRYTRQKQNLPDSPlRFDGlpaVLGSPGFSSGRHRWQVEVqlGDGGGCTVGVAGESVRRK 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 171 SN-DLFPEHGFW-ISMKAGAIHANTHLE-RIPASPRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSLElLCPFFCL 247
Cdd:cd15826   82 GEmGLSAEDGVWaVILSHQQCWASTSPGtDLPLSEIPRRVGVALDYEAGTVTLTNAETQEPIFTFTASFSGK-VFPFFAV 160

PRY/SPRY domain in tripartite motif-binding protein 7 (TRIM7); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of tripartite motif-containing protein 7 (TRIM7), also referred to as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90). TRIM7 or GNIP interacts with glycogenin and stimulates its self-glucosylating activity via its SPRY domain. The GNIP gene encodes at least four distinct isoforms of GNIP, of which three (GNIP1, GNIP2, and GNIP3) have the B30.2 domain.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPRL----ACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRKS 171
Cdd:cd13740    1 ELTLDPDSANPRLILSLDLKSVRLGERAQDLPNHPCRfdtnTRVLASCGFSSGRHHWEVEVGSKDGWAFGVARESVRRKG 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 172 NDLF-PEHGFW-ISMKAGAIHANTHLERIPAS-PRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSlELLCPFFCLe 248
Cdd:cd13740   81 LTPFtPEEGVWaLQLNGGQYWAVTSPERTPLScGHLSRVRVALDLEVGAVSFYAAEDMRHIYTFRVNFQ-ERVFPLFSV- 158

                        170
                 ....*....|....*
gi 153791360 249 llgeGESGNVLTICP 263
Cdd:cd13740  159 ----CSTGTYLRIWP 169

PRY/SPRY domain in tripartite motif-binding (TRIM) proteins TRIM50 and TRIM72; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several TRIM proteins, including TRIM72 and TRIM50. TRIM72 (also known as MG53) 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. It is expressed specifically in skeletal muscle and heart, and tethered to the plasma membrane and cytoplasmic vesicles via its interaction with phosphatidylserine. 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  95 EDVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPR----LACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRK 170
Cdd:cd12897   12 ESLTFDPATAHPLLVVSSGGTVVECGLQKQRRASQPErfdkSTCVVASQGFSEGEHYWEVVVGDKPRWALGVIKGTASRK 91

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 171 SN-DLFPEHGFW-ISMKAGAIHaNTHLER-----IPASPRLRRVGIFLDADLEEIQFFDV---DNNVLIYTHDGFFSLEL 240
Cdd:cd12897   92 GKlHASPSHGVWlIGLKEGKVY-EAHGEPkeprpLRVAGRPHRIGVYLSFEDGVLSFFDAsdpDDLRTLYTFQERFQGKL 170

                 ....*
gi 153791360 241 LcPFF 245
Cdd:cd12897  171 Y-PFF 174

PRY/SPRY domain in tripartite motif-binding protein 41 (TRIM41); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of tripartite motif-containing protein 41 (TRIM41). TRIM41 (also known as RING finger-interacting protein with C kinase or RINCK) 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKIHHDLTKDPRL----ACVLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADRKS 171
Cdd:cd13741    1 DLTLDPDTAHPALLLSPDRRGVRLAERRQEVPEHPKRfsadCCVLGAQGFRSGRHYWEVEVGGRRGWAVGAARESTHHKE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 172 NDLFPEHGFWISMKAGAIH------------------------------ANTHLERIPASP--RLRRVGIFLDADLEEIQ 219
Cdd:cd13741   81 KVGSGGSSVSSGDASSSRHhhrrrrlhlpqqpllqrevwcvgtngkryqAQSSTEQTLLSPseKPRRFGVYLDYEAGRLG 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 153791360 220 FFDVDNNVLIYTHDGFFSLELLCPFFclELLGEGESgnvLTICP 263
Cdd:cd13741  161 FYNAETLAHVHTFSAAFLGERVFPFF--RVLSKGTR---IKLCP 199

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 153791360  98 TLDAATASSLLVFSNDLRSAQC---KKIHHDLTKDPRLAC---VLGTPCFSSGQHYWEVEVGEVKSWSLGVCKEPADR-- 169
Cdd:cd13734    2 KLDPKTAHRKLRLSNDNLTVEYdpeGSKDQAAVLPRRFTGspaVLGDVAISSGRHYWEVSVSRSTSYRVGVAYKSAPRde 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 170 ------KSNDLFPEHGFWISMKAGAIHANTHleripaSPRLRRVGIFLDADLEEIQFFDVDNNVLIYTHDGFFSlELLCP 243
Cdd:cd13734   82 dlgknsTSWCLSRDNNRYTARHDGKVVDLRV------TGHPARIGVLLDYDNGTLSFYDAESKQHLYTFHVDFE-GPVCP 154

                 ....
gi 153791360 244 FFCL 247
Cdd:cd13734  155 AFAV 158

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 153791360  93 FREDVTLDAATASSLLVFSNDLRSAQ----------CKKIHHDLTkdprlacVLGTPCFSSGQHYWEVEVGEVKSWSLGV 162
Cdd:cd15823    1 YWVDVTLNPHTANLNLVLSKNRRQVRfvgaklsgpsYLEEHYDCS-------VLGSQHFSSGKHYWEVDVTKKTAWILGV 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 163 CK---EPAdrKSNDLF-----------PEHGFWIsmkAGAIHANTHLERIPASPRL--------RRVGIFLDADLEEIQF 220
Cdd:cd15823   74 CShslGPT--FSFNQYaqnhnaysryqPQSGYWV---IGLQHNHEYRAYEDSSTSLllsmtvppRRVGVFLDYEAGTVSF 148

                        170       180
                 ....*....|....*....|....*.
gi 153791360 221 FDVDNNVL-IYTHDGFFSLELLCPFF 245
Cdd:cd15823  149 YNVTNHGFpIYTFSKYYFPTTLCPYF 174

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 153791360  96 DVTLDAATASSLLVFSNDLRSAQCKKI---HHDLTKDPRLACVLGTPCFSSGQHYWEVEVGEVKSWSLGVC---KEPADR 169
Cdd:cd15810    1 DVTLNPVNISLNIVISEDQRQVRIVPPqtsGQALTNNNYDFGVLGSQYFSSGKHYWEVDVSKKSAWILGVCshkRSDAMT 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 153791360 170 KSNDLF-----------PEHGFW-ISMKAGAIHANTHLERIPASPRL--------RRVGIFLDADLEEIQFFDVDNN-VL 228
Cdd:cd15810   81 KSNANQinhqnvysryqPQYGYWvIGLQNESEYNAFEDSSSFNPHVLtlsvtvppHRVGVFLDYEAGTVSFFNVTNHgSL 160

                        170
                 ....*....|....*..
gi 153791360 229 IYTHDGFFSLELLCPFF 245
Cdd:cd15810  161 IYKFSKCCFSTTVCPYF 177