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 58037095  32 FKLEEKTAHSSLALFRGDTGVKYGLVGLEPTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSR 111
Cdd:cd12903   1 FKLDERTAHSSLDLFKKDTGVIYRMLGVDPTKVPQNPERFRDWAVVLGDTPVTSGRHYWEVTVKRSQEFRIGVADVDMSR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 112 DSCVGADDRSWVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGPVAPAFALW 191
Cdd:cd12903  81 DECIGTNESSWVFAYAQRKWYAMVANETVPVPLVGKPDRVGLLLDYEAGKLSLVDVEKNSVVHTMSAEFRGPVVPAFALW 160

                ....*....
gi 58037095 192 DGELLTHSG 200
Cdd:cd12903 161 DGELLTHSG 169

PRY/SPRY domain containing protein 4 (SPRYD4); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain and is encoded by the SPRYD4 gene. SPRYD4 (SPRY containing domain 4) is ubiquitously expressed in many human tissues, most strongly in kidney, bladder, brain, thymus and stomach. Subcellular localization demonstrates that SPRYD4 protein is localized in the nucleus when overexpressed in COS-7 green monkey cell. It has remained uncharacterized thus far.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  32 FKLEEKTAHSSLALFRGDTGVKYGLVGLEPTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSR 111
Cdd:cd12903   1 FKLDERTAHSSLDLFKKDTGVIYRMLGVDPTKVPQNPERFRDWAVVLGDTPVTSGRHYWEVTVKRSQEFRIGVADVDMSR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 112 DSCVGADDRSWVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGPVAPAFALW 191
Cdd:cd12903  81 DECIGTNESSWVFAYAQRKWYAMVANETVPVPLVGKPDRVGLLLDYEAGKLSLVDVEKNSVVHTMSAEFRGPVVPAFALW 160

                ....*....
gi 58037095 192 DGELLTHSG 200
Cdd:cd12903 161 DGELLTHSG 169

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 58037095    87 RHYWEVTV--KRSQQFRIGVA--DVDMSRDSCVGADDRSWVFS--YAQRKWHSMlaNEKAPIKGIGQPEKVGLLLDYEAK 160
Cdd:pfam00622   1 RHYFEVEIfgQDGGGWRVGWAtkSVPRKGERFLGDESGSWGYDgwTGKKYWAST--SPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110
                  ....*....|....*....|....*....|.
gi 58037095   161 KLSLVDVSRiSVIHTLQT-DFRGPVAPAFAL 190
Cdd:pfam00622  79 TISFTKNGK-SLGYAFRDvPFAGPLFPAVSL 108

PRY/SPRY domain containing protein 4 (SPRYD4); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain and is encoded by the SPRYD4 gene. SPRYD4 (SPRY containing domain 4) is ubiquitously expressed in many human tissues, most strongly in kidney, bladder, brain, thymus and stomach. Subcellular localization demonstrates that SPRYD4 protein is localized in the nucleus when overexpressed in COS-7 green monkey cell. It has remained uncharacterized thus far.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  32 FKLEEKTAHSSLALFRGDTGVKYGLVGLEPTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSR 111
Cdd:cd12903   1 FKLDERTAHSSLDLFKKDTGVIYRMLGVDPTKVPQNPERFRDWAVVLGDTPVTSGRHYWEVTVKRSQEFRIGVADVDMSR 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 112 DSCVGADDRSWVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGPVAPAFALW 191
Cdd:cd12903  81 DECIGTNESSWVFAYAQRKWYAMVANETVPVPLVGKPDRVGLLLDYEAGKLSLVDVEKNSVVHTMSAEFRGPVVPAFALW 160

                ....*....
gi 58037095 192 DGELLTHSG 200
Cdd:cd12903 161 DGELLTHSG 169

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 58037095  38 TAHSSLALFRGDTGVKYGLVGLEPTKVAlnlERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSRD---SC 114
Cdd:cd12874   7 TAHLNLILSDDLRSVRVGDISQHPPEPP---PRFFECWQVLGSQSFSSGRHYWEVDVQDDSSWYVGVTYKSLPRKgkmSN 83

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 115 VGADDRSWVFSYAQRK---WHSmlaNEKAPIKGiGQPEKVGLLLDYEAKKLSLVDVSR-ISVIHTLQTDFRGPVAPAFAL 190
Cdd:cd12874  84 LGRNNGSWCLEWRENEfsaWHN---NPETRLPV-TPPRRLGVFLDCDGGSLSFYGVTDgVQLLYTFKAKFTEPLYPAFWL 159

                ....*..
gi 58037095 191 WDGELLT 197
Cdd:cd12874 160 GEGSTLS 166

PRY/SPRY domain of TRIM18/MID1, also known as FXY or RNF59; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is at the C-terminus of the overall domain architecture of MID1 (also known as FXY, RNF59, TRIM18) gene represented by a RING finger domain (RING), two B-box motifs (BBOX), coiled-coil C-terminal to Bbox domain (BBC) and fibronectin type 3 domain (FN3). Mutations in the human MID1 gene result in X-linked Opitz G/BBB syndrome (OS), a disorder affecting development of midline structures, causing craniofacial, urogenital, gastrointestinal and cardiovascular abnormalities. A unique MID1 gene mutation located in a variable loop in the SPRY domain alters conformation of the binding pocket and may affect the binding affinity to the PRY/SPRY domain.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  32 FKLEEKTAHSSLALFRGDTGVKYGLVGlepTKVALNLERFREWAV--VLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDM 109
Cdd:cd12892   2 FKLDPKSAHRKLKVSHDNLTVERDETS---SKKSHTPERFTSQGSygVAGNVFIDSGRHYWEVVISGSTWYAIGIAYKSA 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 110 SRDSCVGADDRSWVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGPVAPAFA 189
Cdd:cd12892  79 PKHEWIGKNSASWVLCRCNNNWVVRHNSKEIPIEPSPHLRRVGILLDYDNGSLSFYDALNSIHLYTFDIAFAQPVCPTFT 158

                       170
                ....*....|....*...
gi 58037095 190 LWDGELLTHSGLEVPKGL 207
Cdd:cd12892 159 VWNKCLTILTGLPIPDHL 176

PRY/SPRY domain of tripartite motif-binding protein 1 (TRIM1) or MID2; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM1 (also known as MID2 or midline 2). 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. MID2 and MID1 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 MID1 have shown to cause Opitz syndrome, a disorder causing congenital anomalies such as cleft lip and palate as well as heart defects.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  32 FKLEEKTAHSSLALFRGDTGVKYGLVGLEPTKVAlnlERFREWAV--VLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDM 109
Cdd:cd13739   1 FKLDPKMAHKKLKISNDGLQMEKDESSLKKSHTP---ERFSGTGCygAAGNIFIDSGCHYWEVVVGSSTWYAIGIAYKSA 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 110 SRDSCVGADDRSWVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGPVAPAFA 189
Cdd:cd13739  78 PKNEWIGKNSSSWVFSRCNNNFVVRHNNKEMLVDVPPQLKRLGVLLDYDNNMLSFYDPANSLHLHTFEVSFILPVCPTFT 157

                       170
                ....*....|..
gi 58037095 190 LWDGELLTHSGL 201
Cdd:cd13739 158 IWNKSLMILSGL 169

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 58037095  69 ERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSR-----DSCVGADDRSWVFSYAQRKWHSMLANEKAPIK 143
Cdd:cd12904  37 ERFDHWPNALASLSFSSGTHAWVVDVGKSCAYKVGVCYGSLERkgsgnEARLGYNAFSWVFSRYDGEFSFSHNGQHVPLE 116

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
gi 58037095 144 GIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGPVAPAFALWD 192
Cdd:cd12904 117 LLKCPARVGVLLDWPSQELLFYDPDSCTVLHSHREAFAAPLLPVFAVAD 165

PRY/SPRY domain in tripartite motif-binding protein 50 (TRIM50); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM50. 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. It is specifically expressed in gastric parietal cells and may play an essential role in tubulovesicular dynamics. It also interacts with and increases the level of p62, a multifunctional adaptor protein that is implicated in various cellular processes such as the autophagy clearance of polyubiquitinated protein aggregates.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  31 SFKLEEKTAHSSLALFRGDTGVKYGLvglEPTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMS 110
Cdd:cd13743  13 LLKLDPLTAHPMLELSKGNTVVECGL---LAQRLPSNPERFDYSNCVLASRGFSSGKHYWEVVVGSKSKWRLGLIKGTTS 89

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 111 RDSCVGADDRS--WVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSR---ISVIHTLQTDFRGPVA 185
Cdd:cd13743  90 RKGKLNKSPENgvWLIGLKEGRVYEAFANPRVPLPLSTRPQRIGVFLDYEKGELTFYNADSpdeLVPIYTFQAEFQGKLY 169

                ...
gi 58037095 186 PAF 188
Cdd:cd13743 170 PLL 172

PRY/SPRY domain in tripartite motif-containing protein 76 (TRIM76), also called cardiomyopathy-associated protein 5; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM76, a Class I TRIM protein. TRIM76 (also known as cardiomyopathy-associated protein 5 or CMYA5 or myospryn or SPRYD2) is a muscle-specific member of the TRIM superfamily, but lacks the RING domain. It has been suggested that TRIM76 is involved in two distinct processes, protein kinase A signaling and vesicular trafficking. It has also been implicated in Duchenne muscular dystrophy and cardiac disease; gene polymorphism of TRIM76 is associated with left ventricular wall thickness in patients with hypertension while its interactions with M-band titin and calpain 3 link it to tibial and limb-girdle muscular dystrophies.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  29 GISFKLEEKTAHSSLALFRGDTGVKYglvglePTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVD 108
Cdd:cd12898   1 GTRFLLLRETAHPALHISSDRGTVIY------FHERRRKMSSLTECPSVLGEELPSCGQYYWETTVTRCPAYRLGICSSS 74

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 109 MSRDSCVGADDRSW----VFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGPV 184
Cdd:cd12898  75 ASQAGALGEGSTSWclhcVPTSEPCRYTLLHSGIVSDVFVTERPARVGTLLDYNNGRLIFINAESGQLLGIFRHRFAQPC 154

                ....*.
gi 58037095 185 APAFAL 190
Cdd:cd12898 155 HPAFAL 160

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 58037095  29 GISF-KLEEKTAHSSLALFRGDTGVKYGlvglePTKVAL--NLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVA 105
Cdd:cd15818  11 GLSLiTLDPKTAHPNLILSEDLTCVWHG-----DTKQMLpdNPERFDSSVAVLGSEGFTSGKHYWEVEVAKKTKWTLGVV 85

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 106 DVDMSRDSCVgaddrswVFSYAQRKWHSMLANE---KA---PIKGI---GQPEKVGLLLDYEAKKLSLVDVSRISVIHTL 176
Cdd:cd15818  86 RESINRKGNC-------PLSPEDGFWLLRLRNQnelKAldvPSFSLtltSNLNKVGIYLDYEGGQVSFYNANTMSHIYTF 158

                       170
                ....*....|..
gi 58037095 177 QTDFRGPVAPAF 188
Cdd:cd15818 159 SDTFTEKIYPYF 170

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 58037095  34 LEEKTAHSSLALFRGDTGVKyglVGLEPTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSRDS 113
Cdd:cd15819   6 LDPDTAHPALILSEDGRSVT---WGETRQDLPENPERFDSLPCVLGQEGFTSGRHYWEVEVGDRTSWDLGVCRDNVMRKG 82

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 114 --CVGADDRSWVF-SYAQRKWhsMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTL-QTDFRGPVAPAFA 189
Cdd:cd15819  83 rvTLSPENGFWAIrLYGNEYW--ALTSPETPLTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTFpQTAFSGPLRPFFR 160

                ..
gi 58037095 190 LW 191
Cdd:cd15819 161 LW 162

PRY/SPRY domain in tripartite motif-binding protein 20 (TRIM20), also known as pyrin; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM20, which is also known as pyrin or marenostrin. Unlike TRIM domains that are composed of RING/B-box/coiled-coil core, the N-terminal RING domain in TRIM20 is exchanged by a PYRIN domain (PYD), a prime mediator of protein interactions necessary for apoptosis, inflammation and innate immune signaling pathway, and it also harbors a C-terminal B30.2 domain. Mutations in pyrin (TRIM20) are associated with familial Mediterranean fever (FMF), a recessively hereditary periodic fever syndrome, characterized by episodes of inflammation and fever. These mutations cluster in the C-terminal B30.2 domain and therefore it is assumed that pyrin plays a role in the innate immune system by possibly effecting caspase-1-dependent IL-1beta maturation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  34 LEEKTAHSSLAlFRGDtgVKYGLVGLEPTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSRDS 113
Cdd:cd15813  13 LDPETAHPNLI-FSDD--LKSVRLGNKWDRLPDNPERFDSCIIVLGSPSFTSGRHYWEVEVGDKTGWILGVCKASVSRKG 89

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 58037095 114 CVGADDRS--WVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLqTDF--RGPVAPAF 188
Cdd:cd15813  90 SMTLSPENgyWVVMMTKRNEYQASTSPPTRLWLREPPRRVGIFLDYEAGDISFYNVTAKSHIYTF-TSFssSGPLQPIF 167

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 58037095  69 ERFREwAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSRDSCVGADDRSWVFSYAQRKWHSMLANEKAPIKGIGQP 148
Cdd:cd12902  35 DRFSI-SQVLCSQAFSSGQHYWEVDTRQCSHWAVGVASWEMSRDQMLGRTMDSWCIEWKGTGQLSAWHMNKETVLGSDKP 113

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*...
gi 58037095 149 EKVGLLLDYEAKKLSLVDVS-RISVIHTLQTDFRGPVAPAFALWDGEL 195
Cdd:cd12902 114 RVVGIWLDLEEGKLAFYSVAnQERLLHECEVSASSPLHPAFWLYGLEP 161

PRY/SPRY domain in tripartite motif-containing proteins, TRIM9 and TRIM67; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM9 proteins. TRIM9 protein is expressed mainly in the cerebral cortex, and functions as an E3 ubiquitin ligase. It has been shown that TRIM9 is localized to the neurons in the normal human brain and its immunoreactivity in affected brain areas in Parkinson's disease and dementia with Lewy bodies is severely decreased, possibly playing an important role in the regulation of neuronal function and participating in pathological process of Lewy body disease through its ligase. TRIM67 negatively regulates Ras activity via degradation of 80K-H, leading to neural differentiation, including neuritogenesis.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  76 VVLGDTTVTSGRHYWEVTVKR---SQQFRIGVADVDMSRDSCVGADDRSWVFsY--AQRKWHsMLANEKA--PIKGIGQP 148
Cdd:cd12889  39 VVLGSVGFSRGVHYWEVTIDRydgHPDPAFGVARIDVNKDKMLGKDDKGWSM-YidNNRSWF-LHNNEHSnrTEGGITVG 116

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 58037095 149 EKVGLLLDYEAKKLSLvdvsrisvihTLQTDFRGPVA---------PAFALWDGELLT-HSGLEVP 204
Cdd:cd12889 117 SVVGVLLDLDRHTLSF----------YVNDEPQGPIAfrnlpgvfyPAVSLNRNVQVTlHTGLEPP 172

PRY/SPRY domain of tripartite motif-binding protein 14 (TRIM14); This is a TRIM14 domain family 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. TRIM14 domains have yet to be characterized. These B30.2 domains are a more recent adaptation where the SPRY/PRY combination is a possible component of immune defense. It belongs to Class IV TRIM protein family which has members involved in antiviral immunity at various levels of interferon signaling cascade.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  34 LEEKTAHSSLALFRGDTGVKYGLVGLEPTKVALNLERFREwavVLGDTTVTSGRHYWEVTVKRSQQ-FRIGVADVDMSRD 112
Cdd:cd13738   3 LEPDTLHPRLRLSDDRLTVSCGWLGTLGLCPPQRFDKLWQ---VLSRDSFFSGRHYWEVDLQEAGAgWWVGAAYPSIGRK 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 113 SC-----VGADDRSWVFSYAQRKWHSMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVS-RISVIHTLQTDFRGPVAP 186
Cdd:cd13738  80 GDseaarLGWNRQSWCLKRYDLEYWAFHDGQRSRLRPEDDPDRLGVFLDYEAGILSFYDVTgGMTHLHTFRATFQEPLYP 159

                ....*..
gi 58037095 187 AFALWDG 193
Cdd:cd13738 160 ALRLWEG 166

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 58037095  69 ERFREWAVVLGDTTVTSGRHYWEVTVKRSQQ--FRIGVADVDMSRDSCV--GADDRSWVFSYAQRKWHSMLANEKAPIKG 144
Cdd:cd15812  36 DRFLAYPCAVGQETFSSGRHYWEVGMNLTGDalWALGVCRDNVSRKDRVpkSPENGFWVVQLSKGKKYLSAMSALTPVTL 115

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 58037095 145 IGQPEKVGLLLDYEAKKLSLVDVSRISVIHTL-QTDFRGPVAPAFAL 190
Cdd:cd15812 116 TEPPSHMGIFLDFEAGEVSFYSVNDGSHLHTYsQAAFPGPLQPFFCL 162

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 58037095  69 ERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSRDSC--VGADDRSWVFSYAQRKWHSMLANeKAPIKgiG 146
Cdd:cd15811  36 ERFDPGPCVLGRERFTSGRHYWEVEVGDRTSWALGVCKENVNRKEKgeLSAGNGFWILVFLGNYYSSERRT-FAPLR--D 112

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 58037095 147 QPEKVGLLLDYEAKKLSLVDVSRISVIHTL-QTDFRGPVAPAFA 189
Cdd:cd15811 113 PPRRVGIFLDYEAGHLSFYSATDGSLLFIFpETPFSGTLRPLFS 156

PRY/SPRY domain in tripartite motif-binding protein 62 (TRIM62); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM62. It is also called DEAR1 ductal epithelium (associated RING chromosome 1) and 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 and thus, making TRIM62 a predictive biomarker. Non-small cell lung cancer lesions show a step-wise loss of TRIM62 levels during disease progression, indicating that it may play a role in the evolution of lung cancer. Decreased levels of TRIM62 also represent an independent adverse prognostic factor in AML.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095  31 SFKLEEKTAHSSLALFRGDTGVKYGlvGLEPTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMS 110
Cdd:cd13744  13 ALTLDPVTAHQRLILSDDCTIVAYG--NLHPQPLQDSPKRFDVEVSVLGSEGFSGGVHYWEVVVSEKTQWMIGLAHEAVS 90

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 111 RDS-----------CVGADDRSWvFSYAQRKWHSMLANEKApikgigqpEKVGLLLDYEAKKLSLVDVSRISVIHTLQTD 179
Cdd:cd13744  91 RKGsiqiqpgrgfyCIVMHDGNQ-YSACTEPWTRLNVKSKL--------EKVGVYLDYDKGLLIFYNADDMSWLYTFREK 161

                       170
                ....*....|
gi 58037095 180 FRGPVAPAFA 189
Cdd:cd13744 162 FPGKLCSYFS 171

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 58037095  34 LEEKTAHSSLALFRGDTGVKYGlvglePTKVAL--NLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSR 111
Cdd:cd13745   7 LDPDTAHPNLVLSEDRKSVRHG-----DTRQDLpdNPERFDTYPCVLGAEGFTGGRHYWEVEVGDKTEWTLGVCRESVSR 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 112 DSCVgaddrswVFSYAQRKWHSMLANEK--------APIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFRGP 183
Cdd:cd13745  82 KGEV-------TLSPENGYWTVWLRDGKyealtsppTPLPVSVRPSRVGIFLDYEAGEVSFYNVTDRSHLFTFTDTFSGT 154

                ....*
gi 58037095 184 VAPAF 188
Cdd:cd13745 155 LRPYF 159

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 58037095  38 TAHSSLALFRGDTGVKYGLVglePTKVALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDMSR--DSCV 115
Cdd:cd12888   8 TAHPRLVLSEDRKSVRWGDT---RQDLPDNPERFDTWPCVLGCEGFTSGRHYWEVEVGDGGGWAVGVARESVRRkgEISF 84

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 116 GADDRSWvfsyAQRKWH---SMLANEKAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDF--RGPVAPAFAL 190
Cdd:cd12888  85 SPEEGIW----AVGQWGgqyWALTSPETPLPLSEVPRRIRVYLDYEGGQVAFFDADNEAPIFTFPPASfaGERIFPWFWV 160

                ....*..
gi 58037095 191 WDGELLT 197
Cdd:cd12888 161 GKGSQLK 167

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 58037095  34 LEEKTAHSSLALFRGDTGVKYglvglepTK----VALNLERFREWAVVLGDTTVTSGRHYWEVTVKRSQQFRIGVADVDM 109
Cdd:cd15829  23 LDPETAHPNLLVSEDKKCVTF-------TKkkqrVPDSPKRFTVNPVVLGFPGFHSGRHFWEVEVGDKPEWAVGVCKDSL 95

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 58037095 110 SRdscvGADDRSwvfSYAQRKWHSMLANE--------KAPIKGIGQPEKVGLLLDYEAKKLSLVDVSRISVIHTLQTDFR 181
Cdd:cd15829  96 ST----KARRPP---SGQQGCWRIQLQGGdydapgavPPPLLLEVKPRGIGVFLDYELGEISFYNMPEKSHIHTFTDTFS 168

                ....*..
gi 58037095 182 GPVAPAF 188
Cdd:cd15829 169 GPLRPYF 175

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 58037095    87 RHYWEVTV--KRSQQFRIGVA--DVDMSRDSCVGADDRSWVFS--YAQRKWHSMlaNEKAPIKGIGQPEKVGLLLDYEAK 160
Cdd:pfam00622   1 RHYFEVEIfgQDGGGWRVGWAtkSVPRKGERFLGDESGSWGYDgwTGKKYWAST--SPLTGLPLFEPGDVIGCFLDYEAG 78

                          90       100       110
                  ....*....|....*....|....*....|.
gi 58037095   161 KLSLVDVSRiSVIHTLQT-DFRGPVAPAFAL 190
Cdd:pfam00622  79 TISFTKNGK-SLGYAFRDvPFAGPLFPAVSL 108

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 58037095  86 GRHYWEVTVKRSQQ--FRIGVA--DVDMSRDSCVGADDRSWVFS-YAQRKWHSmlANEKAPIKGIGQPEKVGLLLDYEAK 160
Cdd:cd11709   1 GKWYWEVRVDSGNGglIQVGWAtkSFSLDGEGGVGDDEESWGYDgSRLRKGHG--GSSGPGGRPWKSGDVVGCLLDLDEG 78

                        90       100       110
                ....*....|....*....|....*....|.
gi 58037095 161 KLS-LVDVSRISVIHTLQTDFRGPVAPAFAL 190
Cdd:cd11709  79 TLSfSLNGKDLGVAFTNLFLKGGGLYPAVSL 109