RING finger (Really Interesting New Gene) domain and U-box domain superfamily; The RING finger is a specialized type of Zn-finger of 40 to 60 residues that binds two atoms of zinc. It is defined by the "cross-brace" motif that chelates zinc atoms by eight amino acid residues, typically Cys or His, arranged in a characteristic spacing. Canonical RING motifs have been categorized into two major subclasses, RING-HC (C3HC4-type) and RING-H2 (C3H2C3-type), according to their Cys/His content. There are also many variants of RING fingers: some have different Cys/His patterns while some lack a single Cys or His residue at typical Zn ligand positions (the fourth or eighth zinc ligand is prevalently exchanged for an Asp, which can indeed chelate Zn in a RING finger as well). C4C4-, C3HC3D-, C2H2C4-, and C3HC5-type RING fingers are closely related to RING-HC fingers. In contrast, C4HC3- (RING-CH alias RINGv), C3H3C2-, C3H2C2D-, C3DHC3-, and C4HC2H-type RING fingers are more closely related to RING-H2 fingers. However, not all RING finger-containing proteins display regular RING finger features, and the RING finger family has turned out to be multifarious. The degenerate RING fingers of the Siz/PIAS RING (SP-RING) family proteins and sporulation protein RMD5, are characterized by lacking the second, fifth, and sixth Zn2+ ion-coordinating residues. They bind only one Zn2+ ion. On the other hand, the RING fingers of the human APC11 and RBX1 proteins can bind a third Zn atom since they harbor four additional Zn ligands. U-box is a modified form of the RING finger domain that lacks metal chelating Cys and His residues. It resembles the cross-brace RING structure consisting of three beta-sheets and a single alpha-helix, which would be stabilized by salt bridges instead of chelated metal ions. U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. RING finger/U-box-containing proteins are a group of diverse proteins with a variety of cellular functions, including oncogenesis, development, viral replication, signal transduction, the cell cycle and apoptosis. Many of them are ubiquitin-protein ligases (E3s) that serve as scaffolds for binding to ubiquitin-conjugating enzymes (E2s, also referred to as ubiquitin carrier proteins or UBCs) in close proximity to substrate proteins, which enable efficient transfer of ubiquitin from E2 to the substrates.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1751221782   9 FQRELTCPICMNYFIDPITIDCGHSFCRPCFYLNWQDITVLVQCSKCKKTTRQRNLRTN 67
Cdd:cd16603     1 FQRELTCPICMNYFIDPVTIDCGHSFCRPCLYLNWQDIPFLAQCPECRKTTEQRNLKTN 59

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM43, TRIM48, TRIM49, TRIM51, TRIM64 and similar proteins; The family includes a group of closely related uncharacterized tripartite motif-containing proteins, TRIM43, TRIM43B, TRIM48/RNF101, TRIM49/RNF18, TRIM49B, TRIM49C/TRIM49L2, TRIM49D/TRIM49L, TRIM51/SPRYD5, TRIM64, TRIM64B, and TRIM64C, whose biological function remain unclear. TRIM49, also known as testis-specific RING-finger protein, has moderate similarity with SS-A/Ro52 antigen, suggesting it may be one of the target proteins of autoantibodies in the sera of patients with these autoimmune disorders. All family members 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 as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. In RBCC region, they all have a C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1751221782   9 FQRELTCPICMNYFIDPITIDCGHSFCRPCFYLNWQDITVLVQCSKCKKTTRQRNLRTN 67
Cdd:cd16603     1 FQRELTCPICMNYFIDPVTIDCGHSFCRPCLYLNWQDIPFLAQCPECRKTTEQRNLKTN 59

Domain in SPla and the RYanodine Receptor; Domain of unknown function. Distant homologues are domains in butyrophilin/marenostrin/pyrin homologues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782  261 SGKYYWEVHVGDSWNWAFGVCnnYWKEKRQNDKIDGEE----GLFLLGCVKEDAHCSLFTTSPLvvqyvPRPTSRVGLFL 336
Cdd:smart00449   1 SGRHYFEVEIGDGGHWRVGVA--TKSVPRGYFALLGEDkgswGYDGDGGKKYHNSTGPEYGLPL-----QEPGDVIGCFL 73

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1751221782  337 DCEGRTMTFVDVDQNALIYTIPNCSFSPPLRPIFCCS 373
Cdd:smart00449  74 DLEAGTISFYKNGKYLHGLAFFDVKFSGPLYPAFSLG 110

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
                  ....*....|....*....|....*....|.
gi 1751221782  15 CPICMNYFIDPITIDCGHSFCRPCFYLNWQD 45
Cdd:pfam15227   1 CPICLDYLEKPVSIECGHSFCLSCINSLQKE 31

DNA repair protein rad18; All proteins in this family for which functions are known are involved in nucleotide excision repair.This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782   6 LQVFQRELTCPICMNYFIDPITIDCGHSFCRPCF--YLNWQDitvlvQCSKCKKTTRQRNLRTNIRLKKMA---SIARKa 80
Cdd:TIGR00599  20 LYPLDTSLRCHICKDFFDVPVLTSCSHTFCSLCIrrCLSNQP-----KCPLCRAEDQESKLRSNWLVSEIVesfKNLRP- 93

                  ....*.
gi 1751221782  81 SLRQFL 86
Cdd:TIGR00599  94 SLLEFL 99

B-Box-type zinc finger;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 1751221782   89 EEQICGTHR-EIKKVFCEVDKSLLCLLCSNSqEHRDHKHCPI 129
Cdd:smart00336   2 RAPKCDSHGdEPAEFFCEECGALLCRTCDEA-EHRGHTVVLL 42

RING finger, HC subclass, found in tripartite motif-containing proteins TRIM43, TRIM48, TRIM49, TRIM51, TRIM64 and similar proteins; The family includes a group of closely related uncharacterized tripartite motif-containing proteins, TRIM43, TRIM43B, TRIM48/RNF101, TRIM49/RNF18, TRIM49B, TRIM49C/TRIM49L2, TRIM49D/TRIM49L, TRIM51/SPRYD5, TRIM64, TRIM64B, and TRIM64C, whose biological function remain unclear. TRIM49, also known as testis-specific RING-finger protein, has moderate similarity with SS-A/Ro52 antigen, suggesting it may be one of the target proteins of autoantibodies in the sera of patients with these autoimmune disorders. All family members 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 as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. In RBCC region, they all have a C3HC4-type RING-HC finger.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1751221782   9 FQRELTCPICMNYFIDPITIDCGHSFCRPCFYLNWQDITVLVQCSKCKKTTRQRNLRTN 67
Cdd:cd16603     1 FQRELTCPICMNYFIDPVTIDCGHSFCRPCLYLNWQDIPFLAQCPECRKTTEQRNLKTN 59

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 1751221782 210 VDFTLQPERANSHIFLYGDLRSINVG--CDPQDDPHFTAKSeCFLVWGAQTFTSGKYYWEVHVGDSWNWAFGVCNNYWKE 287
Cdd:cd15813     9 VNVTLDPETAHPNLIFSDDLKSVRLGnkWDRLPDNPERFDS-CIIVLGSPSFTSGRHYWEVEVGDKTGWILGVCKASVSR 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 288 KRQNDkIDGEEGLFLLGCVKEDAHCSLftTSPLVVQYVPRPTSRVGLFLDCEGRTMTFVDVDQNALIYTIPNCSFSPPLR 367
Cdd:cd15813    88 KGSMT-LSPENGYWVVMMTKRNEYQAS--TSPPTRLWLREPPRRVGIFLDYEAGDISFYNVTAKSHIYTFTSFSSSGPLQ 164

                  ....
gi 1751221782 368 PIFC 371
Cdd:cd15813   165 PIFS 168

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 1751221782 208 FRVDFTLQPERANSHIFLYGDLRSINVGCDPQDDPHFTAKSECF-LVWGAQTFTSGKYYWEVHVGDSWNWAFGVCNNYWK 286
Cdd:cd12900     1 HMVHITLDPDTANPWLILSKDRRQVRLGDTHQNVPENEERFDNYpMVLGAQRFNSGKHYWEVDVTGKEAWDLGVCRDSVR 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 287 EKRQNdKIDGEEGLFLLGCVKEDAHCSLFTTSPLVVQYVPRptsRVGLFLDCEGRTMTFVDV-DQNALIYTIPNCSFSPP 365
Cdd:cd12900    81 RKGQF-LLSPENGFWTIWLWNKKYEAGTSPQTTLHLQVPPC---QVGIFLDYEAGVVSFYNItDHGSLIYTFSECAFTGP 156

                  ....*
gi 1751221782 366 LRPIF 370
Cdd:cd12900   157 LRPFF 161

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 1751221782 211 DFTLQPERANSHIFLYGDLRSINVGCDPQDDPHFTAKSECF-LVWGAQTFTSGKYYWEVHVGDSWNWAFGVCNNYwKEKR 289
Cdd:cd15820     5 DVILDPDTANPILLISEDQRSLQWADEPQNLPDNPKRFDWHyCVLGCKSFTSGRHFWEVEVGDRKEWYVGVCREN-VERK 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 290 QNDKIDGEEGLFLLGCVKEDAHCSLftTSPLVVQYVPRPTSRVGLFLDCEGRTMTFVDVDQNALIYTIPNCSFSPPLRPI 369
Cdd:cd15820    84 LWVKMAPENGFWTIGLSDGNDYQAL--TDPRTKLTIANPPQRVGVFLDYETGEVSFYNAMDGSHIYTFPHTSFSGPLYPV 161

                  .
gi 1751221782 370 F 370
Cdd:cd15820   162 F 162

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 1751221782 210 VDFTLQPERANSHIFLYGDLRSINVGCDPQDDPhftAKSECFL----VWGAQTFTSGKYYWEVHVGDSWNWAFGVCnnyw 285
Cdd:cd15819     2 VNVTLDPDTAHPALILSEDGRSVTWGETRQDLP---ENPERFDslpcVLGQEGFTSGRHYWEVEVGDRTSWDLGVC---- 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 286 kekRQNDKIDG------EEGLFLLGcVKEDAHCSLftTSPLVVQYVPRPTSRVGLFLDCEGRTMTFVDVDQNALIYTIPN 359
Cdd:cd15819    75 ---RDNVMRKGrvtlspENGFWAIR-LYGNEYWAL--TSPETPLTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTFPQ 148

                         170
                  ....*....|..
gi 1751221782 360 CSFSPPLRPIFC 371
Cdd:cd15819   149 TAFSGPLRPFFR 160

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 1751221782 211 DFTLQPERANSHIFLYGDLRSINVGCDPQDDPHFTAKSECFLVWGAQTFTSGKYYWEVHVGDSWNWAFGVCN-------- 282
Cdd:cd15810     1 DVTLNPVNISLNIVISEDQRQVRIVPPQTSGQALTNNNYDFGVLGSQYFSSGKHYWEVDVSKKSAWILGVCShkrsdamt 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 283 --NYWKEKRQND--KIDGEEGLFLLGcVKEDAHCSLFTTS-----PLVVQYVPRPTSRVGLFLDCEGRTMTFVDV-DQNA 352
Cdd:cd15810    81 ksNANQINHQNVysRYQPQYGYWVIG-LQNESEYNAFEDSssfnpHVLTLSVTVPPHRVGVFLDYEAGTVSFFNVtNHGS 159

                         170
                  ....*....|....*...
gi 1751221782 353 LIYTIPNCSFSPPLRPIF 370
Cdd:cd15810   160 LIYKFSKCCFSTTVCPYF 177

PRY/SPRY domain of tripartite motif-binding protein 60 (TRIM60) also known as RING finger protein 33 (RNF33); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM60, which is also known as RING finger protein 33 (RNF33) or 129 (RNF129). TRIM60 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. Based on its expression profile, RNF33 likely plays an important role in the spermatogenesis process, the development of the pre-implantation embryo, and in testicular functions; Rnf33 is temporally transcribed in the unfertilized egg and the pre-implantation embryo, and is permanently silenced before the blastocyst stage. Mice experiments have shown that RNF33 associates with the cytoplasmic motor proteins, kinesin-2 family members 3A (KIF3A) and 3B (KIF3B), suggesting possible contribution to cargo movement along the microtubule in the expressed sites.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 202 LDRL-SGFRVDFTLQPERANSHIFLYGDLRSINVGCDPQDDPHFTAK-SECFLVWGAQTFTSGKYYWEVHVGDSWNWAFG 279
Cdd:cd15828     1 LDRIiKRFQVDVTLDPETAHPQLTVSEDRKSVLYGEMKQNVCYNPRRfYLCPAVLGSEGFHSGRQYWEVEVGDKPEWTLG 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 280 VCNNYWKEKRQNdKIDGEEGLFllgCVKEDAHCSLFTTSPLVVQYVPRPT-SRVGLFLDCEGRTMTFVDVDQNALIYTIP 358
Cdd:cd15828    81 VCQDCLPRNWSN-QPSVQDGLW---AIGRYSESNYVALGPKKIQLLPKVRpSKIGIFLDYELGEVSFYNMNDRSLLYTFS 156

                         170
                  ....*....|...
gi 1751221782 359 NCsFSPPLRPIFC 371
Cdd:cd15828   157 DS-FTGTLWPYFY 168

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 1751221782 210 VDFTLQPERANSHIFLYGDLRSINVGCDPQ----DDPHFTAksecFLVWGAQTFTSGKYYWEVHVGDSWNWAFGVC---N 282
Cdd:cd15824     3 VDVMLNPVNAVSNVVVSADQRQVTVVHICMfrnsNPCDFSA----FDVLGCQYFSSGKYYWEVDVSGKIAWILGVYskrN 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 283 NYWKEK-----------RQN--DKIDGEEGLFLLGCVKE---DAHCSLFTTSPLVVQ-YVPRPTSRVGLFLDCEGRTMTF 345
Cdd:cd15824    79 NLNKRKssgfafdpnvnHPNvySRYRPQNGYWVIGLQNEseyNAFEDSSSSDPKVLTlSMAVPPHRVGVFLDYEAGTVSF 158

                         170       180
                  ....*....|....*....|....*.
gi 1751221782 346 VDV-DQNALIYTIPNCSFSPPLRPIF 370
Cdd:cd15824   159 FNVtNHGSLIYKFSKCCFSQPVYPYF 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 1751221782 212 FTLQPERANSHIFLYGDLRSINVG----CDPQDDPHFTaksECFLVWGAQTFTSGKYYWEVHVGDSWNWAFGVCnnYWKE 287
Cdd:cd12874     1 LTFDPDTAHLNLILSDDLRSVRVGdisqHPPEPPPRFF---ECWQVLGSQSFSSGRHYWEVDVQDDSSWYVGVT--YKSL 75

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 288 KRQNDKID-GEEGLFLLGCVKEDAhcslFTTSPLVVQYV--PRPTSRVGLFLDCEGRTMTFVDV-DQNALIYTIpNCSFS 363
Cdd:cd12874    76 PRKGKMSNlGRNNGSWCLEWRENE----FSAWHNNPETRlpVTPPRRLGVFLDCDGGSLSFYGVtDGVQLLYTF-KAKFT 150

                  ....*..
gi 1751221782 364 PPLRPIF 370
Cdd:cd12874   151 EPLYPAF 157

RING finger, HC subclass, found in tripartite motif-containing proteins, TRIM7, TRIM11 and TRIM27, and similar proteins; TRIM7, TRIM11 and TRIM27, 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, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM7, also known as glycogenin-interacting protein (GNIP) or RING finger protein 90 (RNF90), is an E3 ubiquitin-protein ligase that mediates c-Jun/AP-1 activation by Ras signalling. Its phosphorylation and activation by MSK1 in response to direct activation by the Ras-Raf-MEK-ERK pathway can stimulate TRIM7 E3 ubiquitin ligase activity in mediating Lys63-linked ubiquitination of the AP-1 coactivator RACO-1, leading to RACO-1 protein stabilization. Moreover, TRIM7 binds and activates glycogenin, the self-glucosylating initiator of glycogen biosynthesis. TRIM11, also known as protein BIA1, or RING finger protein 92 (RNF92), is an E3 ubiquitin-protein ligase involved in the development of the central nervous system. It is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 acts as a potential therapeutic target for congenital central hypoventilation syndrome (CCHS) by mediating the degradation of CCHS-associated polyalanine-expanded Phox2b. TRIM11 modulates the function of neurogenic transcription factor Pax6 through the ubiquitin-proteosome system, and thus plays an essential role for Pax6-dependent neurogenesis. It also binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105), humanin, a neuroprotective peptide against Alzheimer's disease-relevant insults, and further regulates ARC105 function in transforming growth factor beta (TGFbeta) signaling. Moreover, TRIM11 negatively regulates retinoic acid-inducible gene-I (RIG-I)-mediated interferon-beta (IFNbeta) production and antiviral activity by targeting TANK-binding kinase-1 (TBK1). It may contribute to the endogenous restriction of retroviruses in cells. It enhances N-tropic murine leukemia virus (N-MLV) entry by interfering with Ref1 restriction. It also suppresses the early steps of human immunodeficiency virus HIV-1 transduction, resulting in decreased reverse transcripts. TRIM27, also known as RING finger protein 76 (RNF76), RET finger protein (RFP), or zinc finger protein RFP, is a nuclear E3 ubiquitin-protein ligase that is highly expressed in testis and in various tumor cell lines. Expression of TRIM27 is associated with prognosis of colon and endometrial cancers. TRIM27 was first identified as a fusion partner of the RET receptor tyrosine kinase. It functions as a transcriptional repressor and associates with several proteins involved in transcriptional activity, such as enhancer of polycomb 1 (Epc1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex, and the cell cycle regulator retinoblastoma protein (RB1). It also interacts with HDAC1, leading to downregulation of thioredoxin binding protein 2 (TBP-2), which inhibits the function of thioredoxin. Moreover, TRIM27 mediates Pax7-induced ubiquitination of MyoD in skeletal muscle atrophy. In addition, it inhibits muscle differentiation by modulating serum response factor (SRF) and Epc1. TRIM27 promotes a non-canonical polyubiquitination of PTEN, a lipid phosphatase that catalyzes PtdIns(3,4,5)P3 (PIP3) to PtdIns(4,5)P2 (PIP2). It is an IKKepsilon-interacting protein that regulates IkappaB kinase (IKK) function and negatively regulates signaling involved in the antiviral response and inflammation. TRIM27 also forms a protein complex with MBD4 or MBD2 or MBD3, and thus plays an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis. It is a component of an estrogen receptor 1 (ESR1) regulatory complex that is involved in estrogen receptor-mediated transcription in MCF-7 cells.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1751221782   9 FQRELTCPICMNYFIDPITIDCGHSFCRPCFYLNWQDITVLVQCSKCKKTTRQRNLRTN 67
Cdd:cd16594     2 LQEELTCPICLDYFTDPVTLDCGHSFCRACIARCWEEPETSASCPQCRETCPQRNLRPN 60

PRY/SPRY domain in tripartite motif-containing protein 27 (TRIM27), also known as RING finger protein 76 (RNF76); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM27, also known as RING finger protein 76 (RNF76) or RET finger protein (RFP). TRIM27 domain is composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It is highly expressed in the spleen, thymus and in cells of the hematopoietic compartment. TRIM27 exhibits either nuclear or cytosolic localization depending on the cell type. TRIM27 negatively regulates nucleotide-binding oligomerization domain containing 2 (NOD2)-mediated signaling by proteasomal degradation of NOD2, suggesting that TRIM27 could be a new target for therapeutic intervention in NOD2-associated diseases such as Crohn's. High expression of TRIM27 is observed in several human cancers, including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Also, TRIM27 forms an oncogenic fusion protein with Ret proto-oncogene. It is involved in different stages of spermatogenesis and its significant expression in male germ cells and seminomas, suggests that TRIM27 may be associated with the regulation of testicular germ cell proliferation and histological-type of germ cell tumors. TRIM27 could also be a predictive marker for chemoresistance in ovarian cancer patients. In the neurotoxin model of Parkinson's disease (PD), deficiency of TRIM27 decreases apoptosis and protects dopaminergic neurons, making TRIM27 an effective potential target during the treatment of PD.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 210 VDFTLQPERANSHIFLYGDLRSINVGCDPQDDPHFTAKSECF-LVWGAQTFTSGKYYWEVHVGDSWNWAFGVCNNYWKEK 288
Cdd:cd15814     2 VDVTLDPDTAYPSLILSDNLRQVRYSYLQQDLPDNPERFNLFpCVLGSPCFIAGRHYWEVEVGDKAKWTIGVCEDSVCRK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 289 RQNDKIDgEEGLFLLGCVKEDAHCSLftTSPLVVQYVPRPTSRVGLFLDCEGRTMTFVDVDQNALIYTIPNCSFSPPLRP 368
Cdd:cd15814    82 GGVTSAP-QNGFWAVSLWYGKEYWAL--TSPMTALPLRTPLQRVGIFLDYDAGEVSFYNVTERCHTFTFSHATFCGPVRP 158

                  ....*.
gi 1751221782 369 IFCCSH 374
Cdd:cd15814   159 YFSLSY 164

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 1751221782 213 TLQPERANSHIFLYGDLRSINVGCDPQDDPHFTAK-SECFLVWGAQTFTSGKYYWEVHVGDSWNWAFGVCNNyWKEKRQN 291
Cdd:cd12905     7 TFDPETAHPSLILSRDLTAVTESDEMQPYPRSPKRfLQCVNVLASQGFQSGRHYWEVWVGSKTKWDLGVASE-SVDRQAR 85

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 292 DKIDGEEGLFLLGcVKEDAHCSLFTT--SPLVVQYVPRptsRVGLFLDCEGRTMTFVDVDQNALIYtipncSFSPPLRPI 369
Cdd:cd12905    86 VKLCPENGYWTLR-LRNGDEYWAGTQpwTRLRVTSRPQ---RIGVFLDCEERKVSFYNADDMSLLY-----SFHQGPRGK 156

                  ..
gi 1751221782 370 FC 371
Cdd:cd12905   157 VF 158

RING finger, HC subclass, found in tripartite motif-containing protein TRIM4 and similar proteins; TRIM4 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, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM4, also known as RING finger protein 87 (RNF87), is a cytoplasmic E3 ubiquitin-protein ligase that has recently evolved and is present only in higher mammals. It transiently interacts with mitochondria, induces mitochondrial aggregation and sensitizes the cells to hydrogen peroxide (H2O2) induced death. Its interaction with peroxiredoxin 1 (PRX1) is critical for the regulation of H2O2 induced cell death. Moreover, TRIM4 functions as a positive regulator of RIG-I-mediated type I interferon induction. It regulates the K63-linked ubiquitination of RIG-1 and assembly of antiviral signaling complex at the mitochondria.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1751221782  10 QRELTCPICMNYFIDPITIDCGHSFCRPCFYLNWQDITVLVQCSKCKKTTRQRNLRTN 67
Cdd:cd16590     4 QEELTCPICLDYFQDPVSIECGHNFCRGCLHRNWAPGGGPFPCPECRHPSAPAALRPN 61

PRY/SPRY domain of tripartite motif-binding protein 60 and 75 (TRIM60 and TRIM75); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM60 and TRIM75, both composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM60 domain is also known as RING finger protein 33 (RNF33) or 129 (RNF129). Based on its expression profile, RNF33 likely plays an important role in the spermatogenesis process, the development of the pre-implantation embryo, and in testicular functions; Rnf33 is temporally transcribed in the unfertilized egg and the pre-implantation embryo, and is permanently silenced before the blastocyst stage. Mice experiments have shown that RNF33 associates with the cytoplasmic motor proteins, kinesin-2 family members 3A (KIF3A) and 3B (KIF3B), suggesting possible contribution to cargo movement along the microtubule in the expressed sites. TRIM75, also known as Gm794, has a single site of positive selection in its RING domain associated with E3 ubiquitin ligase activity. It has not been detectably expressed experimentally due to their constant turnover by the proteasome, and therefore not been characterized.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 211 DFTLQPERANSHIFLYGDLRSI-----NVGCdPQDDPHFTAkseCFLVWGAQTFTSGKYYWEVHVGDSWNWAFGVCNNYW 285
Cdd:cd15817     1 DLILDPETAHPNLIVSEDRKAVryrrmKPNC-PYDPRRFTV---YPAVLGSEGFDSGRHFWEVEVGGKGEWILGVCKDSL 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 286 KEKRQnDKIDGEEGLFLLGCVKEDAHCSLFTTSPLVVQYVPRptsRVGLFLDCEGRTMTFVDVDQNALIYTIPNCsFSPP 365
Cdd:cd15817    77 PRNAQ-DPPSPLGGCWQIGRYMSGYVASGPKTTQLLPVVKPS---RIGIFLDYELGEVSFYNMNDRSHLYTFTDT-FTGK 151

                  ....*
gi 1751221782 366 LRPIF 370
Cdd:cd15817   152 LIPYF 156

Domain in SPla and the RYanodine Receptor; Domain of unknown function. Distant homologues are domains in butyrophilin/marenostrin/pyrin homologues.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782  261 SGKYYWEVHVGDSWNWAFGVCnnYWKEKRQNDKIDGEE----GLFLLGCVKEDAHCSLFTTSPLvvqyvPRPTSRVGLFL 336
Cdd:smart00449   1 SGRHYFEVEIGDGGHWRVGVA--TKSVPRGYFALLGEDkgswGYDGDGGKKYHNSTGPEYGLPL-----QEPGDVIGCFL 73

                           90       100       110
                   ....*....|....*....|....*....|....*..
gi 1751221782  337 DCEGRTMTFVDVDQNALIYTIPNCSFSPPLRPIFCCS 373
Cdd:smart00449  74 DLEAGTISFYKNGKYLHGLAFFDVKFSGPLYPAFSLG 110

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 1751221782 211 DFTLQPERANSHIFLYGDLRSINVGCDPQ---DDPHFTAKSECFLvwGAQTFTSGKYYWEVHVGDSWNWAFGVCNNYWKE 287
Cdd:cd12897    13 SLTFDPATAHPLLVVSSGGTVVECGLQKQrraSQPERFDKSTCVV--ASQGFSEGEHYWEVVVGDKPRWALGVIKGTASR 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 288 KRQNDKIDgEEGLFLLGCvKE----DAHCSlfTTSPLVVQYVPRPTsRVGLFLDCEGRTMTFVDVDQN---ALIYTIpNC 360
Cdd:cd12897    91 KGKLHASP-SHGVWLIGL-KEgkvyEAHGE--PKEPRPLRVAGRPH-RIGVYLSFEDGVLSFFDASDPddlRTLYTF-QE 164

                         170
                  ....*....|....*
gi 1751221782 361 SFSPPLRPIF-CCSH 374
Cdd:cd12897   165 RFQGKLYPFFdVCWH 179

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1751221782 211 DFTLQPERANSHIFLYGDLRSINVGCDPQDDP----HFTAKSECFLVWGaqtFTSGKYYWEVHVGDSWNWAFGVCNNYWK 286
Cdd:cd13740     1 ELTLDPDSANPRLILSLDLKSVRLGERAQDLPnhpcRFDTNTRVLASCG---FSSGRHHWEVEVGSKDGWAFGVARESVR 77