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 564330170 288 FEGLMDIQRYWVHVT--PcQYNKEIVsINKNKGQIQCASHYRRNRQVSETFHLGVVGYPAIQSGKHYWEVDVSTCDAWLL 365
Cdd:cd15822    1 FNELTDVQRYWVHVTldP-SNNKNIV-ISEDRRQVRYVRKQQRYNSNGNNEDYGVLGSPSITSGKHYWEVDVSKKRAWIL 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 366 GLSDGKCAQPHLMGemgFKMKLNSNFNQIEMYQPKCGYWVIGMKDRSVYNAFDECSiTHNPSVLVLCLPHAPSRVGVFVD 445
Cdd:cd15822   79 GVCGGKYPNSTLKD---FNKQGKNNQKQCSNYQPKYGYWVIGLQNKSEYNAFEDSS-SSDPLILTLSLTVPPCRVGVFLD 154

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 564330170 446 REACTLSFYDVSNSGALIYRFYYPSFPHRVFPYFNPLECLKPMTVC 491
Cdd:cd15822  155 YEAGTVSFFNVTNHGFLIYKFSSCSFSQEVFPYFNPMKCPVPMTLC 200

B-box-type 2 zinc finger found in tripartite motif-containing proteins, TRIM5, TRIM6, TRIM22, TRIM34, TRIM38 and similar proteins; The family includes TRIM5, TRIM6, TRIM22, TRIM34, and TRIM38, all of which belong to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif. TRIM5, also termed RING finger protein 88 (RNF88), is a capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. Its retroviral restriction activity correlates with the ability to activate TAK1-dependent innate immune signaling. TRIM5 also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Moreover, TRIM5 plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2. It also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction. TRIM6, also termed RING finger protein 89 (RNF89), is an E3-ubiquitin ligase that cooperates with the E2-ubiquitin conjugase UbE2K to catalyze the synthesis of unanchored K48-linked polyubiquitin chains, and further stimulates the interferon-I kappa B kinase epsilon (IKKepsilon) kinase-mediated antiviral response. It also regulates the transcriptional activity of Myc during the maintenance of embryonic stem (ES) cell pluripotency, and may act as a novel regulator for Myc-mediated transcription in ES cells. TRIM22, also termed 50 kDa-stimulated trans-acting factor (Staf-50), or RING finger protein 94 (RNF94), is an E3 ubiquitin-protein ligase that plays an integral role in the host innate immune response to viruses. It has been shown to inhibit the replication of a number of viruses, including HIV-1, hepatitis B, and influenza A. TRIM22 acts as a suppressor of basal HIV-1 long terminal repeat (LTR)-driven transcription by preventing transcription factor specificity protein 1 (Sp1) binding to the HIV-1 promoter. It also controls FoxO4 activity and cell survival by directing Toll-like receptor 3 (TLR3)-stimulated cells toward type I interferon (IFN) type I gene induction or apoptosis. Moreover, TRIM22 can activate the noncanonical nuclear factor-kappaB (NF-kappaB) pathway by activating I kappa B kinase alpha (IKKalpha). It also regulates nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-kappaB. TRIM34, also termed interferon-responsive finger protein 1, or RING finger protein 21 (RNF21), may function as an antiviral protein that contributes to the defense against retroviral infections. TRIM38, also known as RING finger protein 15 (RNF15) or zinc finger protein RoRet, is an E3 ubiquitin-protein ligase that promotes K63- and K48-linked ubiquitination of cellular proteins and also catalyzes self-ubiquitination. It negatively regulates tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta-triggered nuclear factor-kappaB (NF-kappaB) activation by mediating lysosomal-dependent degradation of transforming growth factor beta (TGFbeta)-activated kinase 1 (TAK1)-binding protein (TAB)2/3, two critical components of the TAK1 kinase complex. It also inhibits TLR3/4-mediated activation of NF-kappaB and interferon regulatory factor 3 (IRF3) by mediating ubiquitin-proteasomal degradation of TNF receptor-associated factor 6 (Traf6) and NAK-associated protein 1 (Nap1), respectively. Moreover, TRIM38 negatively regulates TLR3-mediated interferon beta (IFN-beta) signaling by targeting ubiquitin-proteasomal degradation of TIR domain-containing adaptor inducing IFN-beta (TRIF). It functions as a valid target for autoantibodies in primary Sjogren's Syndrome.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 564330170  95 VCAQHGEKLQLFCKKDKMAICWLCERSQEHHGHKTALVE 133
Cdd:cd19761    2 HCEHHGEKLLLFCQEDGKVICWLCERSQEHRGHHTFLLE 40

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 288 FEGLMDIQRYWVHVT--PcQYNKEIVsINKNKGQIQCASHYRRNRQVSETFHLGVVGYPAIQSGKHYWEVDVSTCDAWLL 365
Cdd:cd15822    1 FNELTDVQRYWVHVTldP-SNNKNIV-ISEDRRQVRYVRKQQRYNSNGNNEDYGVLGSPSITSGKHYWEVDVSKKRAWIL 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 366 GLSDGKCAQPHLMGemgFKMKLNSNFNQIEMYQPKCGYWVIGMKDRSVYNAFDECSiTHNPSVLVLCLPHAPSRVGVFVD 445
Cdd:cd15822   79 GVCGGKYPNSTLKD---FNKQGKNNQKQCSNYQPKYGYWVIGLQNKSEYNAFEDSS-SSDPLILTLSLTVPPCRVGVFLD 154

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 564330170 446 REACTLSFYDVSNSGALIYRFYYPSFPHRVFPYFNPLECLKPMTVC 491
Cdd:cd15822  155 YEAGTVSFFNVTNHGFLIYKFSSCSFSQEVFPYFNPMKCPVPMTLC 200

B-box-type 2 zinc finger found in tripartite motif-containing proteins, TRIM5, TRIM6, TRIM22, TRIM34, TRIM38 and similar proteins; The family includes TRIM5, TRIM6, TRIM22, TRIM34, and TRIM38, all of which belong to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif. TRIM5, also termed RING finger protein 88 (RNF88), is a capsid-specific restriction factor that prevents infection from non-host-adapted retroviruses in a species-specific manner by binding to and destabilizing the retroviral capsid lattice before reverse transcription is completed. Its retroviral restriction activity correlates with the ability to activate TAK1-dependent innate immune signaling. TRIM5 also acts as a pattern recognition receptor that activates innate immune signaling in response to the retroviral capsid lattice. Moreover, TRIM5 plays a role in regulating autophagy through activation of autophagy regulator BECN1 by causing its dissociation from its inhibitors BCL2 and TAB2. It also plays a role in autophagy by acting as a selective autophagy receptor which recognizes and targets HIV-1 capsid protein p24 for autophagic destruction. TRIM6, also termed RING finger protein 89 (RNF89), is an E3-ubiquitin ligase that cooperates with the E2-ubiquitin conjugase UbE2K to catalyze the synthesis of unanchored K48-linked polyubiquitin chains, and further stimulates the interferon-I kappa B kinase epsilon (IKKepsilon) kinase-mediated antiviral response. It also regulates the transcriptional activity of Myc during the maintenance of embryonic stem (ES) cell pluripotency, and may act as a novel regulator for Myc-mediated transcription in ES cells. TRIM22, also termed 50 kDa-stimulated trans-acting factor (Staf-50), or RING finger protein 94 (RNF94), is an E3 ubiquitin-protein ligase that plays an integral role in the host innate immune response to viruses. It has been shown to inhibit the replication of a number of viruses, including HIV-1, hepatitis B, and influenza A. TRIM22 acts as a suppressor of basal HIV-1 long terminal repeat (LTR)-driven transcription by preventing transcription factor specificity protein 1 (Sp1) binding to the HIV-1 promoter. It also controls FoxO4 activity and cell survival by directing Toll-like receptor 3 (TLR3)-stimulated cells toward type I interferon (IFN) type I gene induction or apoptosis. Moreover, TRIM22 can activate the noncanonical nuclear factor-kappaB (NF-kappaB) pathway by activating I kappa B kinase alpha (IKKalpha). It also regulates nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-kappaB. TRIM34, also termed interferon-responsive finger protein 1, or RING finger protein 21 (RNF21), may function as an antiviral protein that contributes to the defense against retroviral infections. TRIM38, also known as RING finger protein 15 (RNF15) or zinc finger protein RoRet, is an E3 ubiquitin-protein ligase that promotes K63- and K48-linked ubiquitination of cellular proteins and also catalyzes self-ubiquitination. It negatively regulates tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta-triggered nuclear factor-kappaB (NF-kappaB) activation by mediating lysosomal-dependent degradation of transforming growth factor beta (TGFbeta)-activated kinase 1 (TAK1)-binding protein (TAB)2/3, two critical components of the TAK1 kinase complex. It also inhibits TLR3/4-mediated activation of NF-kappaB and interferon regulatory factor 3 (IRF3) by mediating ubiquitin-proteasomal degradation of TNF receptor-associated factor 6 (Traf6) and NAK-associated protein 1 (Nap1), respectively. Moreover, TRIM38 negatively regulates TLR3-mediated interferon beta (IFN-beta) signaling by targeting ubiquitin-proteasomal degradation of TIR domain-containing adaptor inducing IFN-beta (TRIF). It functions as a valid target for autoantibodies in primary Sjogren's Syndrome.

                         10        20        30
                 ....*....|....*....|....*....|....*....
gi 564330170  95 VCAQHGEKLQLFCKKDKMAICWLCERSQEHHGHKTALVE 133
Cdd:cd19761    2 HCEHHGEKLLLFCQEDGKVICWLCERSQEHRGHHTFLLE 40

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 564330170   15 CPICLELLKEPVSTDCNHSFCRACItinYESNRNTEGEG-SCPVC 58
Cdd:pfam15227   1 CPICLDYLEKPVSIECGHSFCLSCI---NSLQKEPDGESlLCPQC 42

Ring finger; E3 ubiquitin-protein ligase activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain; Various RING fingers exhibit binding activity towards E2 ubiquitin-conjugating enzymes (Ubc' s)

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 564330170    15 CPICLE-LLKEPVSTDCNHSFCRACITINYESNRNTegegsCPVC 58
Cdd:smart00184   1 CPICLEeYLKDPVILPCGHTFCRSCIRKWLESGNNT-----CPIC 40

B-Box-type zinc finger;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 564330170    91 QKVNVCAQHG-EKLQLFCKKDKMAICWLCERSqEHHGHKTALV 132
Cdd:smart00336   1 QRAPKCDSHGdEPAEFFCEECGALLCRTCDEA-EHRGHTVVLL 42

B-Box C-terminal domain; Coiled coil region C-terminal to (some) B-Box domains

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170   140 KEKLQDALQKLMEKEKTCDEWQDVIQQQRTYWENQIQSDIKNVQIEINGLRELLDSKENEELQELKKEKEDVFQRLEESE 219
Cdd:smart00502   2 REALEELLTKLRKKAAELEDALKQLISIIQEVEENAADVEAQIKAAFDELRNALNKRKKQLLEDLEEQKENKLKVLEQQL 81

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 564330170   220 NELVQQRESVRDCISDVEHQLELST-MEMLQSVEYVLRRSQTL 261
Cdd:smart00502  82 ESLTQKQEKLSHAINFTEEALNSGDpTELLLSKKLIIERLQNL 124

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170   119 ERSQEHHGHKTALVEEVDHEYKEKLQDALQKLMEKEKTCDEWQDVIQQQrtywenqiQSDIKNVQIEINGLRELLDSKeN 198
Cdd:TIGR02168  739 EAEVEQLEERIAQLSKELTELEAEIEELEERLEEAEEELAEAEAEIEEL--------EAQIEQLKEELKALREALDEL-R 809

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 564330170   199 EELQELKKEKEDVFQRLEESENELVQQRESVRDC---ISDVEHQLELSTMEMLQSVE 252
Cdd:TIGR02168  810 AELTLLNEEAANLRERLESLERRIAATERRLEDLeeqIEELSEDIESLAAEIEELEE 866

zinc finger-like protein; Provisional

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 564330170   9 IKEEVTCPICLELL-KEPVSTD--------CNHSFCRACITINYESNRNTEGEGSCPVCRVcyLFRNL 67
Cdd:PHA02926 167 VSKEKECGICYEVVySKRLENDryfglldsCNHIFCITCINIWHRTRRETGASDNCPICRT--RFRNI 232

TPR/MLP1/MLP2-like protein; The sequences featured in this family are similar to a region of human TPR protein and to yeast myosin-like proteins 1 (MLP1) and 2 (MLP2). These proteins share a number of features; for example, they all have coiled-coil regions and all three are associated with nuclear pores. TPR is thought to be a component of nuclear pore complex- attached intra-nuclear filaments, and is implicated in nuclear protein import. Moreover, its N-terminal region is involved in the activation of oncogenic kinases, possibly by mediating the dimerization of kinase domains or by targeting these kinases to the nuclear pore complex. MLP1 and MLP2 are involved in the process of telomere length regulation, where they are thought to interact with proteins such as Tel1p and modulate their activity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170  132 VEEVDHEYKEKLQDALQKLmekEKTCDEWQDViqqQRTYwENQIQSDIKNVQiEINGLRELLdSKENEELQELKKEKEDV 211
Cdd:pfam07926  13 LKEEAADAEAQLQKLQEDL---EKQAEIAREA---QQNY-ERELVLHAEDIK-ALQALREEL-NELKAEIAELKAEAESA 83

                          90       100       110
                  ....*....|....*....|....*....|
gi 564330170  212 FQRLEESENELVQQRESVRDCISDVEHQLE 241
Cdd:pfam07926  84 KAELEESEESWEEQKKELEKELSELEKRIE 113

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 288 FEGLMDIQRYWVHVT--PcQYNKEIVsINKNKGQIQCASHYRRNRQVSETFHLGVVGYPAIQSGKHYWEVDVSTCDAWLL 365
Cdd:cd15822    1 FNELTDVQRYWVHVTldP-SNNKNIV-ISEDRRQVRYVRKQQRYNSNGNNEDYGVLGSPSITSGKHYWEVDVSKKRAWIL 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 366 GLSDGKCAQPHLMGemgFKMKLNSNFNQIEMYQPKCGYWVIGMKDRSVYNAFDECSiTHNPSVLVLCLPHAPSRVGVFVD 445
Cdd:cd15822   79 GVCGGKYPNSTLKD---FNKQGKNNQKQCSNYQPKYGYWVIGLQNKSEYNAFEDSS-SSDPLILTLSLTVPPCRVGVFLD 154

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 564330170 446 REACTLSFYDVSNSGALIYRFYYPSFPHRVFPYFNPLECLKPMTVC 491
Cdd:cd15822  155 YEAGTVSFFNVTNHGFLIYKFSSCSFSQEVFPYFNPMKCPVPMTLC 200

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 297 YWVHVTPCQYNK-EIVSINKNKGQIQCASHYR-RNRQVSETFHLGVVGYPAIQSGKHYWEVDVSTCDAWLLGLSdGKCAQ 374
Cdd:cd15824    1 YWVDVMLNPVNAvSNVVVSADQRQVTVVHICMfRNSNPCDFSAFDVLGCQYFSSGKYYWEVDVSGKIAWILGVY-SKRNN 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 375 PHLMGEMGFKMKLNSNFNQI-EMYQPKCGYWVIGMKDRSVYNAFDECSiTHNPSVLVLCLPHAPSRVGVFVDREACTLSF 453
Cdd:cd15824   80 LNKRKSSGFAFDPNVNHPNVySRYRPQNGYWVIGLQNESEYNAFEDSS-SSDPKVLTLSMAVPPHRVGVFLDYEAGTVSF 158

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 564330170 454 YDVSNSGALIYRFYYPSFPHRVFPYFNPLECLKPMTVCGP 493
Cdd:cd15824  159 FNVTNHGSLIYKFSKCCFSQPVYPYFNPWNCPAPMTLCPP 198

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 564330170   7 EMIKEEVTCPICLELLKEPVSTDCNHSFCRACITINYESNRNTEGEGSCPVCRVCYLFRNLRPNRHVANIVE 78
Cdd:cd16591    1 VNIKEEVTCPICLELLTEPLSLDCGHSFCQACITANHKESVNQEGESSCPVCRTSYQPENLRPNRHLANIVE 72

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 564330170 337 HLGVVGYPAIQSGKHYWEVDVSTCDAWLLGLsdgkcAQPHLMGEMGFKMklnsnfnqiemyQPKCGYWVIGMKDRSVYNA 416
Cdd:cd13733   41 CVCVLGSEGFSSGRHYWEVEVGGKTDWDLGV-----ARESVNRKGKITL------------SPENGYWTVGLRNGNEYKA 103

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 417 FDEcsithnPSVLvLCLPHAPSRVGVFVDREACTLSFYDVSNsGALIYRFyYPSFPHRVFPYFNPL-----ECLKPMTVC 491
Cdd:cd13733  104 LTS------PSTP-LSLREKPQKVGVFLDYEEGQVSFYNVDD-GSHIYTF-TDCFTEKLYPYFSPClndggKNSAPLIIC 174

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 564330170 313 INKNKGQIQCaSHYRRNRQ-VSETFH--LGVVGYPAIQSGKHYWEVDVSTCDAWLLGLsdgkCaqphlmgemgfkmkLNS 389
Cdd:cd15821   19 ISEDLRSVRC-GCFRQNRKeLAERFDdaLCVLGSPRFTSGRHYWEVDVGTSTEWDLGV----C--------------RES 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 390 NFNQ--IEMyQPKCGYWVIGMKDRSVYNAfdecSITHnpsVLVLCLPHAPSRVGVFVDREACTLSFYDVSNsGALIYRFY 467
Cdd:cd15821   80 VNRQgpIEL-SPEHGFWTVSLRDGSVFFA----STVP---LTVLWVNPRLHRVGIFLDMEMGTISFYDVSD-GSHIFTFT 150

                        170       180
                 ....*....|....*....|....*...
gi 564330170 468 YPSFPHRVFPYFNPLECLK----PMTVC 491
Cdd:cd15821  151 KISAEEPLRPFFAPANPYGddqgVLSIC 178

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 564330170 340 VVGYPAIQSGKHYWEVDVSTCDAWLLGLsdgkCaqphlmgemgfkmKLNSNFNQIEMYQPKCGYWVIGMKDRSVYNAfde 419
Cdd:cd15813   53 VLGSPSFTSGRHYWEVEVGDKTGWILGV----C-------------KASVSRKGSMTLSPENGYWVVMMTKRNEYQA--- 112

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 564330170 420 csITHNPSVLVLCLPhaPSRVGVFVDREACTLSFYDVSNSgALIYRFYYPSFPHRVFPYFNPL-----ECLKPMTVC 491
Cdd:cd15813  113 --STSPPTRLWLREP--PRRVGIFLDYEAGDISFYNVTAK-SHIYTFTSFSSSGPLQPIFSPGthdggKNMDPLTIC 184

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 564330170 340 VVGYPAIQSGKHYWEVDVSTCDAWLLGLSDGKcaqphlMGEMGFKMKLNSNFnqiemyqpkcGYWVIGMKDrsvynafDE 419
Cdd:cd12874   43 VLGSQSFSSGRHYWEVDVQDDSSWYVGVTYKS------LPRKGKMSNLGRNN----------GSWCLEWRE-------NE 99

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 564330170 420 CSITHNPSVLVLClPHAPSRVGVFVDREACTLSFYDVSNSGALIYRFyYPSFPHRVFPYFNPLEClKPMTVC 491
Cdd:cd12874  100 FSAWHNNPETRLP-VTPPRRLGVFLDCDGGSLSFYGVTDGVQLLYTF-KAKFTEPLYPAFWLGEG-STLSIC 168

RING finger, HC subclass, found in tripartite motif-containing protein TRIM25 and similar proteins; TRIM25, also known as estrogen-responsive finger protein (EFP), RING finger protein 147 (RNF147), or RING-type E3 ubiquitin transferase, is an E3 ubiquitin/ISG15 ligase that is induced by estrogen and is therefore particularly abundant in placenta and uterus. TRIM25 regulates various cellular processes through E3 ubiquitin ligase activity, transferring ubiquitin and ISG15 to target proteins. It mediates K63-linked polyubiquitination of retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. It is also required for melanoma differentiation-associated gene 5 (MDA5) and mitochondrial antiviral signaling (MAVS, also known as IPS-1, VISA, Cardiff) mediated activation of nuclear factor-kappaB (NF-kappaB) and interferon production. Upon UV irradiation, TRIM25 interacts with mono-ubiquitinated PCNA and promotes its ISG15 modification (ISGylation), suggesting a crucial role in termination of error-prone translesion DNA synthesis. TRIM25 also functions as a novel regulator of p53 and Mdm2. It enhances p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26S proteasomes. Meanwhile, it inhibits p53's transcriptional activity and dampens the response to DNA damage, and is essential for medaka development and this dependence is rescued by silencing of p53. Moreover, TRIM25 is involved in the host cellular innate immune response against retroviral infection. It interferes with the late stage of feline leukemia virus (FeLV) replication. Furthermore, TRIM25 acts as an oncogene in gastric cancer. Its blockade by RNA interference inhibits migration and invasion of gastric cancer cells through transforming growth factor-beta (TGF-beta) signaling, suggesting it presents a novel target for the detection and treatment of gastric cancer. In addition, TRIM25 acts as an RNA-specific activator for Lin28a/TuT4-mediated uridylation. TRIM25 belongs to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 564330170  10 KEEVTCPICLELLKEPVSTDCNHSFCRACITINYESNRNteGEGSCPVCRVCYLFR-NLRPNRHVANIVER 79
Cdd:cd16597    3 EEELTCSICLELFKDPVTLPCGHNFCGVCIEKTWDSQHG--SEYSCPQCRATFPRRpELHKNTVLRNIVEQ 71

RING finger, HC subclass, found in tripartite motif-containing protein 26 (TRIM26) and similar proteins; TRIM26, also known as acid finger protein (AFP), RING finger protein 95 (RNF95), or zinc finger protein 173 (ZNF173), is an E3 ubiquitin-protein ligase that negatively regulates interferon-beta production and antiviral response through polyubiquitination and degradation of nuclear transcription factor IRF3. It functions as an important regulator for RNA virus-triggered innate immune response by bridging TBK1 to NEMO (NF-kappaB essential modulator, also known as IKKgamma) and mediating TBK1 activation. It also acts as a novel tumor suppressor of hepatocellular carcinoma by regulating cancer cell proliferation, colony forming ability, migration, and invasion. TRIM26 belongs the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, a B-box, and two coiled coil domains, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 564330170   9 IKEEVTCPICLELLKEPVSTDCNHSFCRACITiNYESNRNTEGEGSCPVCRVCYLFRNLRPNR 71
Cdd:cd16598    1 LEEEVTCSICLDYLRDPVTIDCGHNFCRSCIT-DYCPISGGHERPVCPLCRKPFKKENIRPNW 62

RING finger, HC subclass, found in tripartite motif-containing protein TRIM17 and similar proteins; TRIM17, also known as RING finger protein 16 (RNF16) or testis RING finger protein (Terf), is a crucial E3 ubiquitin ligase that is necessary and sufficient for neuronal apoptosis and contributes to Mcl-1 ubiquitination in cerebellar granule neurons (CGNs). It interacts in a SUMO-dependent manner with nuclear factor of activated T cell NFATc3 transcription factor, and thus inhibits the activity of NFATc3 by preventing its nuclear localization. In contrast, it binds to and inhibits NFATc4 transcription factor in a SUMO-independent manner. Moreover, TRIM17 stimulates degradation of kinetochore protein ZW10 interacting protein (ZWINT), a known component of the kinetochore complex required for the mitotic spindle checkpoint, and negatively regulates cell proliferation. TRIM17 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 564330170   9 IKEEVTCPICLELLKEPVSTDCNHSFCRACITINYESNRNTEGEGS------CPVCRVCYLFRNLRPNR 71
Cdd:cd16595    2 LQEEATCSICLDYFTDPVMTTCGHNFCRACIQLSWEKARGKKGRRKqkgsfpCPECREMSPQRNLRPNR 70

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 564330170 310 IVSINKNKGQIQCASHYRRNRQVSETFHLG--VVGYPAIQSGKHYWEVDVSTCDAWLLGLSDGKCAQphlmgemgfKMKL 387
Cdd:cd13743   24 MLELSKGNTVVECGLLAQRLPSNPERFDYSncVLASRGFSSGKHYWEVVVGSKSKWRLGLIKGTTSR---------KGKL 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 388 NSNfnqiemyqPKCGYWVIGMKDRSVYNAFDecsithNPSVlVLCLPHAPSRVGVFVDREACTLSFYDVSNSGAL--IYR 465
Cdd:cd13743   95 NKS--------PENGVWLIGLKEGRVYEAFA------NPRV-PLPLSTRPQRIGVFLDYEKGELTFYNADSPDELvpIYT 159

                        170
                 ....*....|....*
gi 564330170 466 FyYPSFPHRVFPYFN 480
Cdd:cd13743  160 F-QAEFQGKLYPLLD 173

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 564330170 340 VVGYPAIQSGKHYWEVDVSTCDAWLLGLsdgkcaqphLMGEMGFKMKLNSNfnqiemyqPKCGYWVIGMKDRSVYNAFDE 419
Cdd:cd12897   56 VVASQGFSEGEHYWEVVVGDKPRWALGV---------IKGTASRKGKLHAS--------PSHGVWLIGLKEGKVYEAHGE 118

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 564330170 420 CSithnpSVLVLCLPHAPSRVGVFVDREACTLSFYDVSNSGALIYRF-YYPSFPHRVFPYFN 480
Cdd:cd12897  119 PK-----EPRPLRVAGRPHRIGVYLSFEDGVLSFFDASDPDDLRTLYtFQERFQGKLYPFFD 175

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 564330170 337 HLGVVGYPAIQSGKHYWEVDVSTCDAWLLGLSDGKCaqphlmgEMGFKMKLNsnfnqiemyqPKCGYWVIGMKDRSVYNA 416
Cdd:cd15820   45 HYCVLGCKSFTSGRHFWEVEVGDRKEWYVGVCRENV-------ERKLWVKMA----------PENGFWTIGLSDGNDYQA 107

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 564330170 417 FDEcSITHnpsvlvLCLPHAPSRVGVFVDREACTLSFYDVSNsGALIYRFYYPSFPHRVFPYF 479
Cdd:cd15820  108 LTD-PRTK------LTIANPPQRVGVFLDYETGEVSFYNAMD-GSHIYTFPHTSFSGPLYPVF 162

RING finger, HC subclass, found in tripartite motif-containing protein 35 (TRIM35) and similar proteins; TRIM35, also known as hemopoietic lineage switch protein 5 (HLS5), is a putative hepatocellular carcinoma (HCC) suppressor that inhibits phosphorylation of pyruvate kinase isoform M2 (PKM2), which is involved in aerobic glycolysis of cancer cells and further suppresses the Warburg effect and tumorigenicity in HCC. It also negatively regulates Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon production by suppressing the stability of interferon regulatory factor 7 (IRF7). Moreover, TRIM35 regulates erythroid differentiation by modulating globin transcription factor 1 (GATA-1) activity. TRIM35 belongs to the C-IV subclass of the TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as a B30.2/SPRY (SplA and ryanodine receptor) domain positioned C-terminal to the RBCC domain.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170   9 IKEEVTCPICLELLKEPVSTDCNHSFCRACITINYESnrntEGEGSCPVCRVCYLFRNLRPNRHVANIVE 78
Cdd:cd16599    1 FKEELLCPICYEPFREAVTLRCGHNFCKGCVSRSWER----QPRAPCPVCKEASSSDDLRTNHTLNNLVE 66

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 340 VVGYPAIQSGKHYWEVDVSTCDAWLLGLS----DGKCaqphlmgemgfKMKLNsnfnqiemyqPKCGYWVIGMKDRsvyn 415
Cdd:cd12905   48 VLASQGFQSGRHYWEVWVGSKTKWDLGVAsesvDRQA-----------RVKLC----------PENGYWTLRLRNG---- 102

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564330170 416 afDECSITHNPSVLvLCLPHAPSRVGVFVDREACTLSFYDVSNSgALIYRFYYPSfPHRVFPYFNPleCL-------KPM 488
Cdd:cd12905  103 --DEYWAGTQPWTR-LRVTSRPQRIGVFLDCEERKVSFYNADDM-SLLYSFHQGP-RGKVFPFFST--CFsddgqnaEPM 175

                 ...
gi 564330170 489 TVC 491
Cdd:cd12905  176 RLL 178

RING finger, HC subclass, found in tripartite motif-containing protein 40 (TRIM40) and similar proteins; TRIM40, also known as probable E3 NEDD8-protein ligase or RING finger protein 35 (RNF35), is highly expressed in the gastrointestinal tract including the stomach, small intestine, and large intestine. It enhances neddylation of inhibitor of nuclear factor kappaB kinase subunit gamma (IKKgamma), inhibits the activity of nuclear factor-kappaB (NF-kappaB)-mediated transcription, and thus prevents inflammation-associated carcinogenesis in the gastrointestinal tract. TRIM40 belongs to the C-V subclass of the TRIM (tripartite motif) family of proteins that are defined by an N-terminal RBCC (RING, Bbox, and coiled coil) domain, including three consecutive zinc-binding domains, a C3HC4-type RING-HC finger, Bbox1 and Bbox2, and a coiled coil region, as well as an uncharacterized region positioned C-terminal to the RBCC domain.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 564330170  11 EEVTCPICLELLKEPVSTDCNHSFCRACITINYEsNRNTEGEGSCPVCR 59
Cdd:cd16583    4 EEGVCPICQEPLKEAVSTDCGHLFCRMCLTQHAK-KASASGVFSCPVCR 51