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 1130413365 212 RYYFEVEIF---GAGTYVGLTCKGIDRKGEERNSCisgNNFSWSLQ-WNGKEFTAWYSDMETPLKAGPFRRLGVYIDFPG 287
Cdd:pfam00622   1 RHYFEVEIFgqdGGGWRVGWATKSVPRKGERFLGD---ESGSWGYDgWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEA 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1130413365 288 GILSFYGVEydtMTLVHKFA-CKFSEPVYAAFWLSKKENAIRIVDLG 333
Cdd:pfam00622  78 GTISFTKNG---KSLGYAFRdVPFAGPLFPAVSLGAGEGLKFNFGLR 121

PRY/SPRY domain, also known as B30.2; This domain contains residues in the N-terminus that form a distinct PRY domain structure such that the 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 core); Stonutoxin (secreted poisonous protein of the stonefish Synanceia horrida). 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. Among the TRIM proteins, also known as the N-terminal RING finger/B-box/coiled coil (RBCC) family, only Classes I and II contain the B30.2 domain that has evolved under positive selection. Class I TRIM proteins include multiple members involved in antiviral immunity at various levels of interferon signaling cascade. Among the 75 human TRIMs, roughly half enhance immune response, which they do at multiple levels in signaling pathways. 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 1130413365 159 ITFDPDTAHKYLRLQEENRKVTNTTPWEHPYPdLPSRFLHWRQVLSQQSLYLHRYYFEVEIFG-AGTYVGLTCKGIDRKG 237
Cdd:cd12874     1 LTFDPDTAHLNLILSDDLRSVRVGDISQHPPE-PPPRFFECWQVLGSQSFSSGRHYWEVDVQDdSSWYVGVTYKSLPRKG 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 238 EerNSCISGNNFSWSLQWNGKEFTAWYSDMETPLKAGPFRRLGVYIDFPGGILSFYGVEyDTMTLVHKFACKFSEPVYAA 317
Cdd:cd12874    80 K--MSNLGRNNGSWCLEWRENEFSAWHNNPETRLPVTPPRRLGVFLDCDGGSLSFYGVT-DGVQLLYTFKAKFTEPLYPA 156

                         170
                  ....*....|...
gi 1130413365 318 FWLSkKENAIRIV 330
Cdd:cd12874   157 FWLG-EGSTLSIC 168

Stonustoxin subunit alpha or SNTX subunit alpha; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of Stonustoxin alpha proteins. Stonustoxin (SNTX) is a multifunctional lethal protein isolated from venom elaborated by the stonefish. It comprises two subunits, termed alpha and beta. SNTX elicits an array of biological responses, particularly a potent hypotension and respiratory difficulties.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 149 REQFLQYAYDITFDPDTAHKYLRLQEENRKVTNtTPWEHPYPDLPSRFLHWRQVLSQQSLyLHRYYFEVEIFGAGTYVGL 228
Cdd:cd16040     1 REEFLKYACQLTLDPNTAHRNLSLSEGNRKVTR-VKEEQPYPDHPERFDYWPQVLCREGL-SGRCYWEVEWSGGGVDIAV 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 229 TCKGIDRKGEERNSCISGNNFSWSLQWNGKEFTAWYSDMETPLKA--GPFRRLGVYIDFPGGILSFYGVeYDTMTLVHKF 306
Cdd:cd16040    79 AYKGISRKGDGDDSRFGYNDKSWSLECSPSGYSFWHNNKKTEISVpsSSSSRVGVYLDHSAGTLSFYSV-SDTMTLLHTV 157

                         170
                  ....*....|....
gi 1130413365 307 ACKFSEPVYAAFWL 320
Cdd:cd16040   158 QTTFTEPLYPGFGV 171

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 1130413365 158 DITFDPDTAHKYLRLQEENRKVTNTTPWEHPyPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIfGAGT--YVGLTCKGIDR 235
Cdd:cd13733     1 DVTLDPDTAHPNLILSEDLKSVRYGDKRQNL-PDNPERFDTCVCVLGSEGFSSGRHYWEVEV-GGKTdwDLGVARESVNR 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 236 KGEERNSciSGNNFsWSLQ-WNGKEFTAWySDMETPLK-AGPFRRLGVYIDFPGGILSFYGVeyDTMTLVHKFACKFSEP 313
Cdd:cd13733    79 KGKITLS--PENGY-WTVGlRNGNEYKAL-TSPSTPLSlREKPQKVGVFLDYEEGQVSFYNV--DDGSHIYTFTDCFTEK 152

                         170
                  ....*....|..
gi 1130413365 314 VYAAFWLSKKEN 325
Cdd:cd13733   153 LYPYFSPCLNDG 164

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 1130413365 212 RYYFEVEIF---GAGTYVGLTCKGIDRKGEERNSCisgNNFSWSLQ-WNGKEFTAWYSDMETPLKAGPFRRLGVYIDFPG 287
Cdd:pfam00622   1 RHYFEVEIFgqdGGGWRVGWATKSVPRKGERFLGD---ESGSWGYDgWTGKKYWASTSPLTGLPLFEPGDVIGCFLDYEA 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1130413365 288 GILSFYGVEydtMTLVHKFA-CKFSEPVYAAFWLSKKENAIRIVDLG 333
Cdd:pfam00622  78 GTISFTKNG---KSLGYAFRdVPFAGPLFPAVSLGAGEGLKFNFGLR 121

PRY/SPRY domain in tripartite motif-containing protein 47 (TRIM47), also known as RING finger protein 100 (RNF100) or Gene overexpressed in astrocytoma protein (GOA); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM47, also known as GOA (Gene overexpressed in astrocytoma protein) or RNF100 (RING finger protein 100). TRIM47 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It is highly expressed in kidney tubular cells, but lowly expressed in most tissue. It is overexpressed in astrocytoma tumor cells and plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis; astrocytoma, also known as cerebral astrocytoma, is a malignant glioma that arises from astrocytes. Genome wide studies on white matter lesions have identified a novel locus on chromosome 17q25 harboring several genes such as TRIM47 and TRIM65 which pinpoints to possible novel mechanisms leading to these lesions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 152 FLQYAYDITFDPDTAHKYLRLQeeNRKVTNTTPWEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFGAGTYVGLTCK 231
Cdd:cd15808     3 FLKFAFIVDLDSDTADKFLQLF--GTKGVKRVLCPISYPESPTRFTHCEQVLGEGALDRGTYYWEVEIIEGWVSVGVMAE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 232 GIDRKGEERNSCISGNNFSWSLQWNGKEFTAWYSDMETPLKAGPFRRLGVYIDFPGGILSFYGVEYDTMTLVHKFacKFS 311
Cdd:cd15808    81 DFSPREPYDRGRLGRNAHSCCLQWNGRNFSVWFHGLEAPLPHPFSPTVGVCLEYADRALAFYAVRDGKVSLLRRL--KAS 158

                  ..
gi 1130413365 312 EP 313
Cdd:cd15808   159 RP 160

PRY/SPRY domain in RING finger protein RNF135; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of the RING finger protein RNF135 (also known as Riplet/RNF135), which ubiquitinates RIG-I (retinoic acid-inducible gene-I) to promote interferon-beta induction during the early phase of viral infection. Normally, RIG-I is activated by TRIM25 in response to viral infection, leading to activation of the RIG-I signaling pathway, thus resulting in type I interferon production to limit viral replication. However, RNF135, consisting of an N-terminal RING finger domain, C-terminal SPRY and PRY motifs and showing sequence similarity to TRIM25, acts as an alternative factor that promotes RIG-I activation independent of TRIM25.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 160 TFDPDTAHKYLRLQEENRKVTnTTPWEHPYPDLPSRFlHWRQVLSQQSLYLHRYYFEVEI-FGAGTYVGLTCKGIDRK-- 236
Cdd:cd12902     2 TFDLRSLSCSLEVSEDSRKVT-VSHGPQAYAWSPDRF-SISQVLCSQAFSSGQHYWEVDTrQCSHWAVGVASWEMSRDqm 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 237 -GEERNScisgnnfsWSLQWNGK-EFTAWYSDMETPLKAGPFRRLGVYIDFPGGILSFYGVEyDTMTLVHKFACKFSEPV 314
Cdd:cd12902    80 lGRTMDS--------WCIEWKGTgQLSAWHMNKETVLGSDKPRVVGIWLDLEEGKLAFYSVA-NQERLLHECEVSASSPL 150

                  ....*.
gi 1130413365 315 YAAFWL 320
Cdd:cd12902   151 HPAFWL 156

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 1130413365 156 AYDITFDPDTAHKYLRLQEENRKVTnttpWEHPYPDLPS---RFLHWRQVLSQQSLYLHRYYFEVEIFGAGTY-VGLTCK 231
Cdd:cd15819     1 AVNVTLDPDTAHPALILSEDGRSVT----WGETRQDLPEnpeRFDSLPCVLGQEGFTSGRHYWEVEVGDRTSWdLGVCRD 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 232 GIDRKGEernSCISGNNFSWSLQWNGKEFTAWYSdMETPLK-AGPFRRLGVYIDFPGGILSFYgveydTMT---LVHKFA 307
Cdd:cd15819    77 NVMRKGR---VTLSPENGFWAIRLYGNEYWALTS-PETPLTlKEPPRRVGIFLDYEAGDVSFY-----NMTdgsHIYTFP 147

                         170
                  ....*....|....
gi 1130413365 308 -CKFSEPVYAAFWL 320
Cdd:cd15819   148 qTAFSGPLRPFFRL 161

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 1130413365 159 ITFDPDTAHKYLRLQEENRKVT-NTTPWEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFGAGTY-VGLTckgidRK 236
Cdd:cd13734     1 FKLDPKTAHRKLRLSNDNLTVEyDPEGSKDQAAVLPRRFTGSPAVLGDVAISSGRHYWEVSVSRSTSYrVGVA-----YK 75

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 237 GEERNSCISGNNFSWSLQWNGKEFTAWYSDMETPLKAGPF-RRLGVYIDFPGGILSFYGVEydTMTLVHKFACKFSEPVY 315
Cdd:cd13734    76 SAPRDEDLGKNSTSWCLSRDNNRYTARHDGKVVDLRVTGHpARIGVLLDYDNGTLSFYDAE--SKQHLYTFHVDFEGPVC 153

                  ...
gi 1130413365 316 AAF 318
Cdd:cd13734   154 PAF 156

SPRY domain in Ro-Ret family; This domain, named BSPRY, has been identified in the Ro-Ret family, since the protein is composed of a B-box, an alpha-helical coiled coil and a SPRY domain. The gene for BSPRY resides on human chromosome 9 and is specifically expressed in testis. The function of BSPRY is not known, but several related proteins of the RING-Box-coiled-coil (RBCC) family have been implicated in cell transformation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 159 ITFDPDTAHKYLRLQEENRKVT-NTTPWEHPYPDLPSRFLHWRQVLSQQSLY--LHRYYFEVEIFGAgtY-VGLTCKGID 234
Cdd:cd12904     1 LRFDERTVSPLLSLSEDRRTLTfSPKKARQSPPDDPERFDHWPNALASLSFSsgTHAWVVDVGKSCA--YkVGVCYGSLE 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 235 RKGEERNSCISGNNFSWSLQWNGKEFTAWYSDMETPLKA--GPfRRLGVYIDFPGGILSFYgvEYDTMTLVHKFACKFSE 312
Cdd:cd12904    79 RKGSGNEARLGYNAFSWVFSRYDGEFSFSHNGQHVPLELlkCP-ARVGVLLDWPSQELLFY--DPDSCTVLHSHREAFAA 155

                  ....*.
gi 1130413365 313 PVYAAF 318
Cdd:cd12904   156 PLLPVF 161

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 1130413365 158 DITFDPDTAHKYLRLQEENRKVtNTTPWEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFG-AGTYVGLTCKGIDRK 236
Cdd:cd13741     1 DLTLDPDTAHPALLLSPDRRGV-RLAERRQEVPEHPKRFSADCCVLGAQGFRSGRHYWEVEVGGrRGWAVGAARESTHHK 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 237 ---GEERNSCISGNNFS----------------------WSLQWNGKEFTAWYSDMETPLKAG--PfRRLGVYIDFPGGI 289
Cdd:cd13741    80 ekvGSGGSSVSSGDASSsrhhhrrrrlhlpqqpllqrevWCVGTNGKRYQAQSSTEQTLLSPSekP-RRFGVYLDYEAGR 158

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|.
gi 1130413365 290 LSFYGVEydTMTLVHKFACKF-SEPVYAAFWLSKKENAIRI 329
Cdd:cd13741   159 LGFYNAE--TLAHVHTFSAAFlGERVFPFFRVLSKGTRIKL 197

PRY/SPRY domain in tripartite motif-binding protein 69 (TRIM69), also known as RING finger protein 36 (RNF36); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM69, which is also known as RING finger protein 36 (RNF36) or testis-specific ring finger (Trif). TRIM69 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It 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. The mouse ortholog of this gene is specifically expressed in germ cells at the round spermatid stages during spermatogenesis and, when overexpressed, induces apoptosis. TRIM69 has been shown to be a novel regulator of mitotic spindle assembly in tumor cells; it associates with spindle poles and promotes centrosomal clustering, and is therefore essential for formation of a bipolar spindle.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 159 ITFDPDTAHKYLRLQEENRKVTNTTPwEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFGAGTY-VGLTCKGIDRKG 237
Cdd:cd15818    15 ITLDPKTAHPNLILSEDLTCVWHGDT-KQMLPDNPERFDSSVAVLGSEGFTSGKHYWEVEVAKKTKWtLGVVRESINRKG 93

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 238 eerNSCISGNNFSWSLQW-NGKEFTAwysdMETPLKA----GPFRRLGVYIDFPGGILSFYgvEYDTMTLVHKFACKFSE 312
Cdd:cd15818    94 ---NCPLSPEDGFWLLRLrNQNELKA----LDVPSFSltltSNLNKVGIYLDYEGGQVSFY--NANTMSHIYTFSDTFTE 164

                  ....*.
gi 1130413365 313 PVYAAF 318
Cdd:cd15818   165 KIYPYF 170

PRY/SPRY domain of butyrophilin 3 (BTN3), includes BTN3A1, BTN3A2, BTN3A3 as well as BTN-like 3 (BTNL3); BTN3A also known as CD277; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of butyrophilin family 3A (BTN3A); duplication events have led to three paralogs in primates: BTN3A1, BTN3A2, and BTN3A3. BTNs belong to receptor glycoproteins of immunoglobulin (Ig) superfamily, characterized by the presence of extracellular Ig-like domains (IgV and/or IgC). BTN3 transcripts are ubiquitously present in all immune cells (T cells, B cells, NK cells, monocytes, dendritic cells, and hematopoietic precursors) with different expression levels; BTN3A1 and BTN3A2 are expressed mainly by CD4+ and CD8+ T cells, BTN3A2 is the major form expressed in NK cells, and BTN3A3 is poorly expressed in these immune cells. The PRY/SPRY domain of the BTN3A1 isoform mediates phosphoantigen (pAg)-induced activation by binding directly to the pAg.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 156 AYDITFDPDTAHKYLRLQEENRKVTNTTPwEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFG-AGTYVGLTCKGID 234
Cdd:cd15820     3 PADVILDPDTANPILLISEDQRSLQWADE-PQNLPDNPKRFDWHYCVLGCKSFTSGRHFWEVEVGDrKEWYVGVCRENVE 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 235 RKGEERnscISGNNFSWSLQW-NGKEFTAwYSDMETPLK-AGPFRRLGVYIDFPGGILSFYGVE--YDTMTLVHkfaCKF 310
Cdd:cd15820    82 RKLWVK---MAPENGFWTIGLsDGNDYQA-LTDPRTKLTiANPPQRVGVFLDYETGEVSFYNAMdgSHIYTFPH---TSF 154

                  ....*...
gi 1130413365 311 SEPVYAAF 318
Cdd:cd15820   155 SGPLYPVF 162

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 1130413365 155 YAYDITFDPDTAHKYLRLQEENRKVTNTTPwEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIfGAGTYVGL-TCK-G 232
Cdd:cd13745     1 FAVDVTLDPDTAHPNLVLSEDRKSVRHGDT-RQDLPDNPERFDTYPCVLGAEGFTGGRHYWEVEV-GDKTEWTLgVCReS 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1130413365 233 IDRKGEERNSciSGNNFsWSL-QWNGKeFTAWYSDMeTPL--KAGPfRRLGVYIDFPGGILSFYGV 295
Cdd:cd13745    79 VSRKGEVTLS--PENGY-WTVwLRDGK-YEALTSPP-TPLpvSVRP-SRVGIFLDYEAGEVSFYNV 138

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 1130413365 158 DITFDPDTAHKYLRLQEENRKVTNTTpWEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFGAGTY-VGLTCKGIDRK 236
Cdd:cd15814     3 DVTLDPDTAYPSLILSDNLRQVRYSY-LQQDLPDNPERFNLFPCVLGSPCFIAGRHYWEVEVGDKAKWtIGVCEDSVCRK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 237 GEERNSciSGNNFsWSLQ-WNGKEFTAWYSDMET-PLKAgPFRRLGVYIDFPGGILSFYGV--EYDTMTLVHKFACKFSE 312
Cdd:cd15814    82 GGVTSA--PQNGF-WAVSlWYGKEYWALTSPMTAlPLRT-PLQRVGIFLDYDAGEVSFYNVteRCHTFTFSHATFCGPVR 157

                         170
                  ....*....|....*...
gi 1130413365 313 PVYAAFWLSKKENAIRIV 330
Cdd:cd15814   158 PYFSLSYSGGKSAAPLII 175

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 1130413365 158 DITFDPDTAHKYLRLQEENRKVTNTTPWEHpYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIfGAGTYVGL-TCK-GIDR 235
Cdd:cd15816     1 DVKLDPATAHPSLLLTADLRSVQDGELWRD-VPGNPERFDTWPCVLGLQSFSSGRHYWEVAV-GEKAEWGLgVCQdSAPR 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 236 KGEernSCISGNNFSWSLqW--NGKEFTAWYSDMETPLKAGPFRRLGVYIDFPGGILSFYGVEYDTMtlVHKFACKFSEP 313
Cdd:cd15816    79 KGE---TTPSPENGVWAV-WllKGNEYMVLASPSVPLLQLRRPRRVGVFLDYEAGEISFYNVTAGSH--IYTFRQLFSGI 152

                  ....*..
gi 1130413365 314 VYAAFWL 320
Cdd:cd15816   153 LRPYFFV 159

PRY/SPRY domain in tripartite motif-binding protein 72 (TRIM72); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM72. Muscle-specific TRIM72 (also known as Mitsugumin 53 or 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. TRIM72 interacts with dysferlin, a sarcolemmal protein whose deficiency causes Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B); this coordination plays an important role in the repair of sarcolemma damage.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 158 DITFDPDTAHKYLRLQEENRKVTNTTPWEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFGAGTY-VGLTCKGIDRK 236
Cdd:cd13742    13 NLTFDPDTAHPYLVVSSDGKRVECADQKQAVSSDDPNRFDKANCVVSHQSFSEGEHYWEVIVGDKPRWaLGVISAEAGRK 92

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 237 GeeRNSCISGNNFsWSLQW-NGKEFTAwYSDMETP----LKAGPfRRLGVYIDFPGGILSFY-GVEYDTMTLVHKFACKF 310
Cdd:cd13742    93 G--RLHALPSNGF-WLLGCkEGKVYEA-HVEHKEPralrVEGRP-TRIGVYLSFSDGVLSFYdASDEDNLVQLFAFHERF 167

                         170
                  ....*....|....*....
gi 1130413365 311 SEPVYAAF---WLSKKENA 326
Cdd:cd13742   168 PGPLYPFFdvcWHDKGKNS 186

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 1130413365 158 DITFDPDTAHKYLrLQEENRKVTNTTPWEHPYPDLPSRFLHWRQVLSQQSLYLHRYYFEVEIFGAGTYVGLTCKGIDRKG 237
Cdd:cd15817     1 DLILDPETAHPNL-IVSEDRKAVRYRRMKPNCPYDPRRFTVYPAVLGSEGFDSGRHFWEVEVGGKGEWILGVCKDSLPRN 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1130413365 238 EERNSCIsgNNFSWSLQWNGKEFTAWYSDMETPLKAGPFRRLGVYIDFPGGILSFYgvEYDTMTLVHKFACKFSEPVYAA 317
Cdd:cd15817    80 AQDPPSP--LGGCWQIGRYMSGYVASGPKTTQLLPVVKPSRIGIFLDYELGEVSFY--NMNDRSHLYTFTDTFTGKLIPY 155

                         170
                  ....*....|..
gi 1130413365 318 FWLSKKENAIRI 329
Cdd:cd15817   156 FYVGPDSEPLTI 167