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 189409106 374 DHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDAS-----LTDPLRKFRVLEKNGDGYRALdfcsqnINSEEP 448
Cdd:cd15819   41 DSLPCVLGQEGFTSGRHYWEVEVGDRTSWDLGV---CRDNVMrkgrvTLSPENGFWAIRLYGNEYWAL------TSPETP 111

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 189409106 449 LQLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVPFLGSPYPYF 496
Cdd:cd15819  112 LTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTFPQTAFSGPLRPFF 159

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 189409106 374 DHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDAS-----LTDPLRKFRVLEKNGDGYRALdfcsqnINSEEP 448
Cdd:cd15819   41 DSLPCVLGQEGFTSGRHYWEVEVGDRTSWDLGV---CRDNVMrkgrvTLSPENGFWAIRLYGNEYWAL------TSPETP 111

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 189409106 449 LQLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVPFLGSPYPYF 496
Cdd:cd15819  112 LTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTFPQTAFSGPLRPFF 159

Immunoglobulin V-set domain; This domain is found in antibodies as well as neural protein P0 and CTL4 amongst others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106   37 PAEPITVLLGTEATLPCQLSPEQSAARMHIRWYR----AQPTPAVLVFHNGQeqgevQMPEYRGRTQmVRQAIDMGSVAL 112
Cdd:pfam07686   2 TPREVTVALGGSVTLPCTYSSSMSEASTSVYWYRqppgKGPTFLIAYYSNGS-----EEGVKKGRFS-GRGDPSNGDGSL 75

                          90       100       110
                  ....*....|....*....|....*....|...
gi 189409106  113 QIQQVQASDDGLYHCQ-FTDGFTSQEVSMELRV 144
Cdd:pfam07686  76 TIQNLTLSDSGTYTCAvIPSGEGVFGKGTRLTV 108

Immunoglobulin V-Type;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106    49 ATLPCQLSPEQSAaRMHIRWYRAQPTPAVLVFHNGQEQGEVQ-MPEYRGRTQMVRQAiDMGSVALQIQQVQASDDGLYHC 127
Cdd:smart00406   2 VTLSCKFSGSTFS-SYYVSWVRQPPGKGLEWLGYIGSNGSSYyQESYKGRFTISKDT-SKNDVSLTISNLRVEDTGTYYC 79

                   ..
gi 189409106   128 QF 129
Cdd:smart00406  80 AV 81

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 189409106 374 DHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDAS-----LTDPLRKFRVLEKNGDGYRALdfcsqnINSEEP 448
Cdd:cd15819   41 DSLPCVLGQEGFTSGRHYWEVEVGDRTSWDLGV---CRDNVMrkgrvTLSPENGFWAIRLYGNEYWAL------TSPETP 111

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 189409106 449 LQLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVPFLGSPYPYF 496
Cdd:cd15819  112 LTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTFPQTAFSGPLRPFF 159

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 189409106 374 DHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDASltdplRKFRVLEKNGDGYRAL----DFCSQNINSEEPL 449
Cdd:cd13745   42 DTYPCVLGAEGFTGGRHYWEVEVGDKTEWTLGV---CRESVS-----RKGEVTLSPENGYWTVwlrdGKYEALTSPPTPL 113

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 189409106 450 QLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVpFLGSPYPYF 496
Cdd:cd13745  114 PVSVRPSRVGIFLDYEAGEVSFYNVTDRSHLFTFTDT-FSGTLRPYF 159

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 189409106 352 QDKTDSRTEENRGEETVSSSQVDHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDASltdplRKFRVLEKNGD 431
Cdd:cd15811   17 EDRRSVRRGDLRQALPDSPERFDPGPCVLGRERFTSGRHYWEVEVGDRTSWALGV---CKENVN-----RKEKGELSAGN 88

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 189409106 432 GYRALDFCSQNINSEEP--LQLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVPFLGSPYPYFT 497
Cdd:cd15811   89 GFWILVFLGNYYSSERRtfAPLRDPPRRVGIFLDYEAGHLSFYSATDGSLLFIFPETPFSGTLRPLFS 156

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 189409106 376 NLITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDASltdplRKFRVLEKNGDGYRALDFCSQNINSE----EPLQL 451
Cdd:cd15829   60 NPVVLGFPGFHSGRHFWEVEVGDKPEWAVGV---CKDSLS-----TKARRPPSGQQGCWRIQLQGGDYDAPgavpPPLLL 131

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 189409106 452 KTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVpFLGSPYPYF 496
Cdd:cd15829  132 EVKPRGIGVFLDYELGEISFYNMPEKSHIHTFTDT-FSGPLRPYF 175

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 189409106 374 DHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVY-ELCTQDASLT-DPLRKFRVLE-KNGDGYRALDFCSQNinseepLQ 450
Cdd:cd15818   52 DSSVAVLGSEGFTSGKHYWEVEVAKKTKWTLGVVrESINRKGNCPlSPEDGFWLLRlRNQNELKALDVPSFS------LT 125

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*.
gi 189409106 451 LKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVpFLGSPYPYF 496
Cdd:cd15818  126 LTSNLNKVGIYLDYEGGQVSFYNANTMSHIYTFSDT-FTEKIYPYF 170

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 189409106 380 LSQEGFMLGRYYWEVDVKDTEEWTLGVYELCTQDASLTDPLRKFRV----LEKnGDGYRALdfCSQNInseePLQLKTRP 455
Cdd:cd15816   45 LGLQSFSSGRHYWEVAVGEKAEWGLGVCQDSAPRKGETTPSPENGVwavwLLK-GNEYMVL--ASPSV----PLLQLRRP 117

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 189409106 456 LKIAIFLDQEDNDLSFYNMTDETHIFSFAQVpFLGSPYPYF 496
Cdd:cd15816  118 RRVGVFLDYEAGEISFYNVTAGSHIYTFRQL-FSGILRPYF 157

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 189409106 380 LSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDASltdplRKFRV--LEKNG-------DG--YRALDFCSQNINSEEP 448
Cdd:cd15820   49 LGCKSFTSGRHFWEVEVGDRKEWYVGV---CRENVE-----RKLWVkmAPENGfwtiglsDGndYQALTDPRTKLTIANP 120

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 189409106 449 LQlktrplKIAIFLDQEDNDLSFYNMTDETHIFSFAQVPFLGSPYPYF 496
Cdd:cd15820  121 PQ------RVGVFLDYETGEVSFYNAMDGSHIYTFPHTSFSGPLYPVF 162

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 189409106 384 GFMLGRYYWEVDVKDTEEWTLGVyelCTQDASltdplRKFRVLEKNGDGY-----RALDFCSQNINSEEPLQLKTRPLKI 458
Cdd:cd15821   53 RFTSGRHYWEVDVGTSTEWDLGV---CRESVN-----RQGPIELSPEHGFwtvslRDGSVFFASTVPLTVLWVNPRLHRV 124

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 189409106 459 AIFLDQEDNDLSFYNMTDETHIFSFAQVPFLGSPYPYF 496
Cdd:cd15821  125 GIFLDMEMGTISFYDVSDGSHIFTFTKISAEEPLRPFF 162

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 189409106 380 LSQEGFMLGRYYWEVDVKDTEEWTLGVyelctqdaSLTDPLRKFRV----------LEKNGDGYRALdfcsqnINSEEPL 449
Cdd:cd12888   45 LGCEGFTSGRHYWEVEVGDGGGWAVGV--------ARESVRRKGEIsfspeegiwaVGQWGGQYWAL------TSPETPL 110

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 189409106 450 QLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQVPFLG-SPYPYF 496
Cdd:cd12888  111 PLSEVPRRIRVYLDYEGGQVAFFDADNEAPIFTFPPASFAGeRIFPWF 158

Immunoglobulin Variable (IgV) domain of B7-H3, a member of the B7 family of immune checkpoint molecules; The members here are composed of the immunoglobulin variable (IgV) domain of B7-H3 also known as CD276), a member of the B7 family of immune checkpoint molecules. B7-H3 is an important immune checkpoint member of the B7 family and shares homology with other B7 ligands such as programmed death ligand 1 (PD-L1). The B7 family molecules interact with CD28 on T-cells to provide co-stimulatory signals that regulate T-cell activation and T-helper cell differentiation. Although B7-H3 has been shown to have both co-stimulatory and co-inhibitory effects on T-cell responses, the most current studies describe B7-H3 as a T cell inhibitor that promotes tumor aggressiveness and proliferation. Moreover, B7-H3 is highly overexpressed on a wide range of human solid cancers and promotes tumor growth, metastasis, and drug resistance. Thus, B7-H3 expression in tumors often correlates with both negative prognosis and poor clinical outcome in cancer patients. B7-H3 protein contains a predicted signal peptide, V- and C-like Ig domains (IgV and IgC), a transmembrane region, and an intracellular tail.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106  37 PAEPITVLLGTEATLPCQLSPEQ--SAARMHIRWYRAQPTPAVLVFHNGQEQGEVQMPEYRGRTQMVRQAIDMGSVALQI 114
Cdd:cd20934    3 PEDPVVALVGTDATLRCSFSPEPgfSLAQLSVFWQLTDTKQLVHSFTESQDQGRDQGSAYANRTALFPDLLAQGNASLRL 82

                         90       100
                 ....*....|....*....|....*....
gi 189409106 115 QQVQASDDGLYHCQFT-DGFTSQEVSMEL 142
Cdd:cd20934   83 QRVRVADEGSYTCFVSvQDFGSAAVSLQV 111

PRY/SPRY domain in tripartite motif-binding protein 21 (TRIM21) also known as 52kD Ribonucleoprotein Autoantigen (Ro52); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM21, which is also known as Sjogren Syndrome Antigen A (SSA), SSA1, 52kD Ribonucleoprotein Autoantigen (Ro52, Ro/SSA, SS-A/Ro) or RING finger protein 81 (RNF81). TRIM21 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. As an E3 ligase, TRIM21 mediates target specificity in ubiquitination; it regulates type 1 interferon and proinflammatory cytokines via ubiquitination of interferon regulatory factors (IRFs). It is up-regulated at the site of autoimmune inflammation, such as cutaneous lupus lesions, indicating a central role in the tissue destructive inflammatory process. It interacts with auto-antigens in patients with Sjogren syndrome and systemic lupus erythematosus, a chronic systemic autoimmune disease characterized by the presence of autoantibodies against the protein component of the human intracellular ribonucleoprotein-RNA complexes and more specifically TRIM21, Ro60/TROVE2 and La/SSB proteins. It binds the Fc part of IgG molecules via its PRY-SPRY domain with unexpectedly high affinity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106 378 ITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTqdasltDPLRK---FRVLEKNG--------DGYRAldfcsqNINSE 446
Cdd:cd12900   46 MVLGAQRFNSGKHYWEVDVTGKEAWDLGV---CR------DSVRRkgqFLLSPENGfwtiwlwnKKYEA------GTSPQ 110

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 189409106 447 EPLQLKTRPLKIAIFLDQEDNDLSFYNMTDETH-IFSFAQVPFLGSPYPYF 496
Cdd:cd12900  111 TTLHLQVPPCQVGIFLDYEAGVVSFYNITDHGSlIYTFSECAFTGPLRPFF 161

Immunoglobulin Variable (IgV) domain of B7-H4; The members here are composed of the immunoglobulin variable (IgV) domain of B7-H4 (also known as B7-S1, B7x, or Vtcn1). B7-H4 is one of the B7 family of immune-regulatory ligands that act as negative regulators of T cell function; it contains one IgV domain and one IgC domain. The B7-family consists of structurally related cell-surface protein ligands, which bind to receptors on lymphocytes that regulate immune responses. The binding of B7-H4 to unidentified receptors results in the inhibition of TCR-mediated T cell proliferation, cell-cycle progression and IL-2 production. As a co-inhibitory molecule, B7-H4 is widely expressed in tumor tissues and its expression is significantly associated with poor prognosis in human cancers such as glioma, pancreatic cancer, oral squamous cell carcinoma, renal cell carcinoma, and lung cancer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106  44 LLGTEATLPCQLSPEQSAARMHIRWYRAQPTPAVLVFHNGQEQGEVQMPEYRGRTQMVRQAIDMGSVALQIQQVQASDDG 123
Cdd:cd20984   10 NIGEDGILSCTFTPDIKLSDIVIQWLKEGDSGLVHEFKEGKDELSRQSPMFRGRTSLFADQVHVGNASLRLKNVQLTDAG 89

                         90       100
                 ....*....|....*....|.
gi 189409106 124 LYHCQFTDGFTSQEVSMELRV 144
Cdd:cd20984   90 TYLCIISNSKGTGNANMEYKT 110

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 189409106 374 DHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVYELCTQdasltdplRKFRVLE-----------KNGDGYRALDfcsqn 442
Cdd:cd13743   51 DYSNCVLASRGFSSGKHYWEVVVGSKSKWRLGLIKGTTS--------RKGKLNKspengvwliglKEGRVYEAFA----- 117

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 189409106 443 iNSEEPLQLKTRPLKIAIFLDQEDNDLSFYNM--TDE-THIFSFaQVPFLGSPYPYF 496
Cdd:cd13743  118 -NPRVPLPLSTRPQRIGVFLDYEKGELTFYNAdsPDElVPIYTF-QAEFQGKLYPLL 172

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 189409106 385 FMLGRYYWEVDVKDTEEWTLGVYELCTQDASLTDPLRKFRVLE----------------KNGDGYRALDFCSQNINSEEP 448
Cdd:cd15810   49 FSSGKHYWEVDVSKKSAWILGVCSHKRSDAMTKSNANQINHQNvysryqpqygywviglQNESEYNAFEDSSSFNPHVLT 128

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 189409106 449 LQLKTRPLKIAIFLDQEDNDLSFYNMTDE-THIFSFAQVPFLGSPYPYF 496
Cdd:cd15810  129 LSVTVPPHRVGVFLDYEAGTVSFFNVTNHgSLIYKFSKCCFSTTVCPYF 177

Immunoglobulin Variable (IgV) domain in HERV-H LTR-associating 2 (HHLA2); The members here are composed of the immunoglobulin variable (IgV) region in HERV-H LTR-associating 2 (HHLA2; also known as B7-H7/B7 homolog 7). HHLA2 is a member of the B7 family of immune regulatory proteins. Mature human HHLA2 consists of an extracellular domain (ECD) with three immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic domain. HHLA2 is widely expressed in human cancers including non-small cell lung carcinoma (NSCLS), triple negative breast cancer (TNBC), and melanoma, but has limited expression on normal tissues. Interestingly, unlike other members of B7 family, HHLA2 is not expressed in mice or rats. HHLA2 functions as a T cell coinhibitory molecules as it inhibits the proliferation of activated CD4(+) and CD8(+) T cells and their cytokine production. Furthermore, HHLA2 is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation, however it is not inducible on T cells.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106  40 PITVLLGTEATLPCQLSPeqsAARMHIRWYRAQPTPAVLVFHNGQEQGEVQMPEYRGRTQMVRQAIDMGSVALQIQQVQA 119
Cdd:cd16091    6 IVVCLLSEDCILPCSFTP---GSEVVIHWYKQDSDIKVHSYYYGKDQLESQDQRYRNRTSLFKDQISNGNASLLLRRVQL 82

                 ....*...
gi 189409106 120 SDDGLYHC 127
Cdd:cd16091   83 QDEGRYKC 90

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 189409106 369 SSSQVDHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGV-YELCTQDASLT-DPLRKFR-VLEKNGDGYRAldfCSQNINS 445
Cdd:cd13744   47 SPKRFDVEVSVLGSEGFSGGVHYWEVVVSEKTQWMIGLaHEAVSRKGSIQiQPGRGFYcIVMHDGNQYSA---CTEPWTR 123

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 189409106 446 eepLQLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFAQvPFLGSPYPYFT 497
Cdd:cd13744  124 ---LNVKSKLEKVGVYLDYDKGLLIFYNADDMSWLYTFRE-KFPGKLCSYFS 171

Immunoglobulin V-Type;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106    49 ATLPCQLSPEQSAaRMHIRWYRAQPTPAVLVFHNGQEQGEVQ-MPEYRGRTQMVRQAiDMGSVALQIQQVQASDDGLYHC 127
Cdd:smart00406   2 VTLSCKFSGSTFS-SYYVSWVRQPPGKGLEWLGYIGSNGSSYyQESYKGRFTISKDT-SKNDVSLTISNLRVEDTGTYYC 79

                   ..
gi 189409106   128 QF 129
Cdd:smart00406  80 AV 81

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 189409106 372 QVDHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVY-ELCTQDASLTDP---------LRKFRVLEKNGDGYRALdfcsq 441
Cdd:cd12897   49 RFDKSTCVVASQGFSEGEHYWEVVVGDKPRWALGVIkGTASRKGKLHASpshgvwligLKEGKVYEAHGEPKEPR----- 123

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 189409106 442 ninseePLQLKTRPLKIAIFLDQEDNDLSFYNMTDETH---IFSFaQVPFLGSPYPYF 496
Cdd:cd12897  124 ------PLRVAGRPHRIGVYLSFEDGVLSFFDASDPDDlrtLYTF-QERFQGKLYPFF 174

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 189409106 380 LSQEGFMLGRYYWEVDVKDTEEWTLGVyelCTQDA-SLTD-----PLRKFRVLEKNGDGYRALDFCSQNINSEEPlqlkt 453
Cdd:cd15809   67 LGKNVFTSGKHYWEVENRDSLEIAVGV---CREDVmGITDgsemsPHVGIWAICWSSAGYRPLTSSPVSPTKQEP----- 138

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 189409106 454 RPLKIAIFLDQEDNDLSFYNMTDETHIFSFAqVPFLGSPYPYF 496
Cdd:cd15809  139 ALHRVGVFLDHGAGEVSFYSAVDGVHLHTFS-CPLVSRLRPFF 180

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 189409106 351 DQDKTDSRTEENRGEETVSSSQVDHNLITLSQEGFMLGRYYWEVDVKDTEEWTLGVyelctqdASLTDPlrKFRVLEKNG 430
Cdd:cd13734   17 DNLTVEYDPEGSKDQAAVLPRRFTGSPAVLGDVAISSGRHYWEVSVSRSTSYRVGV-------AYKSAP--RDEDLGKNS 87

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 189409106 431 DGYrALDFCSQNI-----NSEEPLQLKTRPLKIAIFLDQEDNDLSFYNMTDETHIFSFaQVPFLGSPYPYFT 497
Cdd:cd13734   88 TSW-CLSRDNNRYtarhdGKVVDLRVTGHPARIGVLLDYDNGTLSFYDAESKQHLYTF-HVDFEGPVCPAFA 157