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
                 ....*....|....*....|....*....|....*....|....*....
gi 767939046  39 GTLREPVTIDCGHNFCRACLTRYCEIPGPDLEESPTCPLCKEPFRPGSF 87
Cdd:cd16593   13 GTLREPVTIDCGHNFCRACLTRYCEIPGPDLEEPPTCPLCKEPFRPGEF 61

coiled-coil (CC) domain of Drosophila brain tumor (brat) and similar proteins; This family contains the coiled-coil (CC) region of Drosophila brain tumor (Brat), a translational repressor that belongs to the tripartite motif (TRIM) protein superfamily. TRIM proteins play important roles in various cellular processes and are involved in many diseases which consists of two B-box domains and a coiled-coil (CC) domain at the N-terminal region, and an NHL domain at the C-terminus. Brat localizes at the basal cortex during asymmetric division of Drosophila neuroblasts by directly interacting with the scaffolding protein Miranda (Mira), which it does through the CC-NHL domain tandem, indicating that the function of the Brat CC domain is to assemble Brat-NHL in dimeric form which is necessary for Mira binding. Brat CC forms an elongated antiparallel dimer similar to its other TRIM protein counterparts, but the overall length of Brat CC dimer is shorter than the TRIMs.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767939046   161 REQIHKCLKCLRKEREEIQEIQSRENKRMQVLLTQVSTKRQQVISEFAHLRKFLEEQQSILLAQLESQDGDILRQ 235
Cdd:smart00502   2 REALEELLTKLRKKAAELEDALKQLISIIQEVEENAADVEAQIKAAFDELRNALNKRKKQLLEDLEEQKENKLKV 76

SPRY domain; SPRY Domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions. It is a protein-interaction module involved in many important signalling pathways like RNA processing, regulation of histone H3 methylation, innate immunity or embryonic development. It can be divided into 11 subfamilies based on amino acid sequence similarity or the presence of additional protein domains. The greater SPRY family is divided into the SPRY/B30.2 (which contains a PRY extension at the N-terminal) and SPRY-only sub-families which are preceded by a subdomain that is structurally similar to the PRY region. SPRY/B30.2 structures revealed a bent beta-sandwich fold comprised of two beta-sheets. Distant homologs are domains in butyrophilin/ marenostrin/pyrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046  382 RHTWVVSIDLAHGGSCTVGVVSEDVQRKGELRLRPEEGVWAVRLAWG-FVSALGSFPTRLTLKEQPRQVRVSLDYEVGWV 460
Cdd:pfam00622   1 RHYFEVEIFGQDGGGWRVGWATKSVPRKGERFLGDESGSWGYDGWTGkKYWASTSPLTGLPLFEPGDVIGCFLDYEAGTI 80

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 767939046  461 TFTNAvTREPIYTFT-ASFTRKVIPFFGL-WGRGSSFSL 497
Cdd:pfam00622  81 SFTKN-GKSLGYAFRdVPFAGPLFPAVSLgAGEGLKFNF 118

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 767939046   381 GRHTWVVSIDlaHGGSCTVGVVSEDVQRKGELRLRPEEGVWAVRLAWGFVSALGSFP-TRLTLKEQPRQVRVSLDYEVGW 459
Cdd:smart00449   2 GRHYFEVEIG--DGGHWRVGVATKSVPRGYFALLGEDKGSWGYDGDGGKKYHNSTGPeYGLPLQEPGDVIGCFLDLEAGT 79

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 767939046   460 VTFTNAVTREPIYTF-TASFTRKVIPFFGLWGRGS 493
Cdd:smart00449  80 ISFYKNGKYLHGLAFfDVKFSGPLYPAFSLGSGNS 114

B-Box-type zinc finger;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 767939046   112 GEEDVCQEHG-EKIYFFCEDDEMQLCVVCREAgEHATHTMRFL 153
Cdd:smart00336   1 QRAPKCDSHGdEPAEFFCEECGALLCRTCDEA-EHRGHTVVLL 42

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 767939046   41 LREPVTIDCGHNFCRACLTRYCEIPGpdlEESPTCPLC 78
Cdd:pfam15227   8 LEKPVSIECGHSFCLSCINSLQKEPD---GESLLCPQC 42

B-box zinc finger;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 767939046  113 EEDVCQEHG-EKIYFFCEDDEMQLCVVCREaGEHATHTMRFL 153
Cdd:pfam00643   2 KERLCPEHEeEPLTLYCNDCQELLCEECSV-GEHRGHTVVPL 42

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

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 767939046   161 REQIHKCLKCLRKEREEIQEIQSRENKRMQVLLTQVSTKRQQVISEFAHLRKFLEEQQSILLAQLESQDGDILRQ 235
Cdd:smart00502   2 REALEELLTKLRKKAAELEDALKQLISIIQEVEENAADVEAQIKAAFDELRNALNKRKKQLLEDLEEQKENKLKV 76

PRY/SPRY domain in tripartite motif-binding protein 7 (TRIM7)-like, including TRIM7, TRIM10, TRIM15, TRIM26, TRIM39, TRIM41; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several tripartite motif-containing (TRIM) proteins, including TRIM7 (also referred to as glycogenin-interacting protein, RING finger protein 90 or RNF90), TRIM10, TRIM15, TRIM26, TRIM39 and TRIM41. TRIM7 or GNIP interacts with glycogenin and stimulates its self-glucosylating activity via its SPRY domain. TRIM10 (also known as hematopoietic RING finger 1 (HERF1) or TRIM10/HERF1) plays a key role in definitive erythroid development; downregulation of the Spi-1/PU.1 oncogene induces the expression of TRIM10/HERF1, a key factor required for terminal erythroid cell differentiation and survival. Antiviral activity of TRIM15 is dependent on the ability of its B-box to interact with the MLV Gag precursor protein; downregulation of TRIM15, along with TRIM11, enhances virus release suggesting that these proteins contribute to the endogenous restriction of retroviruses in cells. Tripartite motif-containing 26 (TRIM26) function is as yet unknown; however, since it is localized in the human histocompatibility complex (MHC) class I region, TRIM26 may play a role in immune response although studies show no association between TRIM26 polymorphisms and the risk of aspirin-exacerbated respiratory disease. TRIM39 is a MOAP-1 (Modulator of Apoptosis)-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process. TRIM41 (also known as RING finger-interacting protein with C kinase or RINCK) functions as an E3 ligase that catalyzes the ubiquitin-mediated degradation of protein kinase C.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 329 HISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSIDLahGGSCTVGVVSEDVQR 408
Cdd:cd12888    1 NVTLDPDTAHPRLVLSEDRKSVRWGDTRQDLPDNPERFDTWPCVLGCEGFTSGRHYWEVEVGD--GGGWAVGVARESVRR 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 409 KGELRLRPEEGVWAVRLAWGFVSALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFT-ASFTR-KVIPFF 486
Cdd:cd12888   79 KGEISFSPEEGIWAVGQWGGQYWALTSPETPLPLSEVPRRIRVYLDYEGGQVAFFDADNEAPIFTFPpASFAGeRIFPWF 158

                        170
                 ....*....|..
gi 767939046 487 GLWgRGSSFSLS 498
Cdd:cd12888  159 WVG-KGSQLKLC 169

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 767939046 330 ISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVsiDLAHGGSCTVGVVSEDVQRK 409
Cdd:cd13733    2 VTLDPDTAHPNLILSEDLKSVRYGDKRQNLPDNPERFDTCVCVLGSEGFSSGRHYWEV--EVGGKTDWDLGVARESVNRK 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 410 GELRLRPEEGVWAVRLAWGFV-SALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFTASFTRKVIPFFGL 488
Cdd:cd13733   80 GKITLSPENGYWTVGLRNGNEyKALTSPSTPLSLREKPQKVGVFLDYEEGQVSFYNVDDGSHIYTFTDCFTEKLYPYFSP 159

                 ...
gi 767939046 489 WGR 491
Cdd:cd13733  160 CLN 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 767939046 328 AHISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVsiDLAHGGSCTVGVVSEDVQ 407
Cdd:cd15819    2 VNVTLDPDTAHPALILSEDGRSVTWGETRQDLPENPERFDSLPCVLGQEGFTSGRHYWEV--EVGDRTSWDLGVCRDNVM 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 408 RKGELRLRPEEGVWAVRLAWGFVSALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFT-ASFTRKVIPFF 486
Cdd:cd15819   80 RKGRVTLSPENGFWAIRLYGNEYWALTSPETPLTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTFPqTAFSGPLRPFF 159

                 ....*...
gi 767939046 487 GLWGRGSS 494
Cdd:cd15819  160 RLWSSDSG 167

PRY/SPRY domain in tripartite motif-binding protein 69 (TRIM69), also known as RING finger protein 36 (RNF36); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM69, which is also known as RING finger protein 36 (RNF36) or testis-specific ring finger (Trif). TRIM69 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It is a novel testis E3 ubiquitin ligase that may function to ubiquitinate its particular substrates during spermatogenesis. In humans, TRIM69 localizes in the cytoplasm and nucleus, and requires an intact RING finger domain to function. The mouse ortholog of this gene is specifically expressed in germ cells at the round spermatid stages during spermatogenesis and, when overexpressed, induces apoptosis. TRIM69 has been shown to be a novel regulator of mitotic spindle assembly in tumor cells; it associates with spindle poles and promotes centrosomal clustering, and is therefore essential for formation of a bipolar spindle.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 330 ISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSIdlAHGGSCTVGVVSEDVQRK 409
Cdd:cd15818   15 ITLDPKTAHPNLILSEDLTCVWHGDTKQMLPDNPERFDSSVAVLGSEGFTSGKHYWEVEV--AKKTKWTLGVVRESINRK 92

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767939046 410 GELRLRPEEGVWAVRLAWGF-VSALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFTASFTRKVIPFF 486
Cdd:cd15818   93 GNCPLSPEDGFWLLRLRNQNeLKALDVPSFSLTLTSNLNKVGIYLDYEGGQVSFYNANTMSHIYTFSDTFTEKIYPYF 170

PRY/SPRY domain of tripartite motif-binding protein 75 (TRIM75); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM75, also known as Gm794. TRIM75 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM75 has a single site of positive selection in its RING domain associated with E3 ubiquitin ligase activity. It has not been detectably expressed experimentally due to their constant turnover by the proteasome, and therefore not been characterized.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 301 FPQQALPLQREMKMFLEKlcfeldyepahISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITG 380
Cdd:cd15829    3 FPPQYSALQKIIKKFRVD-----------VTLDPETAHPNLLVSEDKKCVTFTKKKQRVPDSPKRFTVNPVVLGFPGFHS 71

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 381 GRHTWVVSIDlaHGGSCTVGVVSEDVQRKGELRLRPEEGVWAVRLAWGFVSALGSFPTRLTLKEQPRQVRVSLDYEVGWV 460
Cdd:cd15829   72 GRHFWEVEVG--DKPEWAVGVCKDSLSTKARRPPSGQQGCWRIQLQGGDYDAPGAVPPPLLLEVKPRGIGVFLDYELGEI 149

                        170       180       190
                 ....*....|....*....|....*....|...
gi 767939046 461 TFTNAVTREPIYTFTASFTRKVIPFFGLwGRGS 493
Cdd:cd15829  150 SFYNMPEKSHIHTFTDTFSGPLRPYFYV-GPDS 181

PRY/SPRY domain of tripartite motif-binding protein 38 (TRIM38), also known as Ring finger protein 15 (RNF15); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM38, which is also known as RING finger protein 15 (RNF15) or RORET. TRIM38 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. TRIM38 has been shown to act as a suppressor in TOLL-like receptor (TLR)-mediated interferon (IFN)-beta induction by promoting degradation of TRAF6 and NAP1 through the ubiquitin-proteasome system. Another study has shown that TRIM38 may act as a novel negative regulator for TLR3-mediated IFN-beta signaling by targeting TRIF for degradation. TRIM38 has been identified as a critical negative regulator in TNFalpha- and IL-1beta-triggered activation of NF-kappaB and MAP Kinases (MAPKs); it causes degradation of two essential cellular components, TGFbeta-associated kinase 1 (TAK1)-associating chaperones 2 and 3 (TAB2/3). The degradation is promoted through a lysosomal-dependent pathway, which requires the C-terminal PRY-SPRY of TRIM38. Enterovirus 71 infection induces degradation of TRIM38, suggesting that TRIM38 may play a role in viral infections.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 330 ISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSIDlaHGGSCTVGVVSEDVQRK 409
Cdd:cd15815   15 VTLDPDTAHPELTLSKDQRQVTYGRCQENLDASPKRFTVLPCVLGCEGFTSGRHYFEVDVG--EGTGWDVGVCLENVQRG 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 410 GELRLRPEEGVWAVRLAW--GFVsALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTF-TASFTRKVIPFF 486
Cdd:cd15815   93 FGMKQEPEFGFWTIRLCEedGYV-ALTSPPTPLPLREKPLVVGVFLDYEAGLVSFYNMTTGSHIFTFpKASFSDTLRPYF 171

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 767939046 330 ISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSIdlAHGGSCTVGVVSEDVQRK 409
Cdd:cd15817    2 LILDPETAHPNLIVSEDRKAVRYRRMKPNCPYDPRRFTVYPAVLGSEGFDSGRHFWEVEV--GGKGEWILGVCKDSLPRN 79

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 767939046 410 GELRLRPEEGVWAVRLAWGFVSALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFTASFTRKVIPFF 486
Cdd:cd15817   80 AQDPPSPLGGCWQIGRYMSGYVASGPKTTQLLPVVKPSRIGIFLDYELGEVSFYNMNDRSHLYTFTDTFTGKLIPYF 156

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 767939046 327 PAHISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSIdlAHGGSCTVGVVSEDV 406
Cdd:cd13743   11 PELLKLDPLTAHPMLELSKGNTVVECGLLAQRLPSNPERFDYSNCVLASRGFSSGKHYWEVVV--GSKSKWRLGLIKGTT 88

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 407 QRKGELRLRPEEGVWAVRLAWGFV-SALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTRE---PIYTFTASFTRKV 482
Cdd:cd13743   89 SRKGKLNKSPENGVWLIGLKEGRVyEAFANPRVPLPLSTRPQRIGVFLDYEKGELTFYNADSPDelvPIYTFQAEFQGKL 168

                 ....
gi 767939046 483 IPFF 486
Cdd:cd13743  169 YPLL 172

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 767939046 327 PAHISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSIdlahgGSCT---VGVVS 403
Cdd:cd12905    3 PAPLTFDPETAHPSLILSRDLTAVTESDEMQPYPRSPKRFLQCVNVLASQGFQSGRHYWEVWV-----GSKTkwdLGVAS 77

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 404 EDVQRKGELRLRPEEGVWAVRLAWGFVSALGSFP-TRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFTASFTRKV 482
Cdd:cd12905   78 ESVDRQARVKLCPENGYWTLRLRNGDEYWAGTQPwTRLRVTSRPQRIGVFLDCEERKVSFYNADDMSLLYSFHQGPRGKV 157

                 ....
gi 767939046 483 IPFF 486
Cdd:cd12905  158 FPFF 161

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 767939046 327 PAHISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVsiDLAHGGSCTVGVVSEDV 406
Cdd:cd12897   11 LESLTFDPATAHPLLVVSSGGTVVECGLQKQRRASQPERFDKSTCVVASQGFSEGEHYWEV--VVGDKPRWALGVIKGTA 88

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 407 QRKGELRLRPEEGVWAVRLAWGFV-SALG--SFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTRE---PIYTFTASFTR 480
Cdd:cd12897   89 SRKGKLHASPSHGVWLIGLKEGKVyEAHGepKEPRPLRVAGRPHRIGVYLSFEDGVLSFFDASDPDdlrTLYTFQERFQG 168

                 ....*.
gi 767939046 481 KVIPFF 486
Cdd:cd12897  169 KLYPFF 174

RING finger, HC subclass, found in tripartite motif-containing protein 10 (TRIM10) and similar proteins; TRIM10, also known as B30-RING finger protein (RFB30), RING finger protein 9 (RNF9), or hematopoietic RING finger 1 (HERF1), is a novel hematopoiesis-specific RING finger protein required for terminal differentiation of erythroid cells. TRIM10 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
                 ....*....|....*....|....*....|....*....|....*....
gi 767939046  39 GTLREPVTIDCGHNFCRACLTRYCEIPGPDLEESPTCPLCKEPFRPGSF 87
Cdd:cd16593   13 GTLREPVTIDCGHNFCRACLTRYCEIPGPDLEEPPTCPLCKEPFRPGEF 61

PRY/SPRY domain in tripartite motif-binding protein 41 (TRIM41); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of tripartite motif-containing protein 41 (TRIM41). TRIM41 (also known as RING finger-interacting protein with C kinase or RINCK) is localized to speckles in the cytoplasm and nucleus, and functions as an E3 ligase that catalyzes the ubiquitin-mediated degradation of protein kinase C.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 330 ISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSI------------DLAH---- 393
Cdd:cd13741    2 LTLDPDTAHPALLLSPDRRGVRLAERRQEVPEHPKRFSADCCVLGAQGFRSGRHYWEVEVggrrgwavgaarESTHhkek 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 394 ----GGSCTVGVVSEDVQRKGELRLRPEEG------VWAVRLAWGFVSALGSFP-TRLTLKEQPRQVRVSLDYEVGWVTF 462
Cdd:cd13741   82 vgsgGSSVSSGDASSSRHHHRRRRLHLPQQpllqreVWCVGTNGKRYQAQSSTEqTLLSPSEKPRRFGVYLDYEAGRLGF 161

                        170       180       190
                 ....*....|....*....|....*....|....*.
gi 767939046 463 TNAVTREPIYTFTASF-TRKVIPFFGLWGRGSSFSL 497
Cdd:cd13741  162 YNAETLAHVHTFSAAFlGERVFPFFRVLSKGTRIKL 197

PRY/SPRY domain in tripartite motif-containing (TRIM) proteins, including TRIM14-like, TRIM16-like, TRIM25-like, TRIM47-like, TRIM65 and RNF135, and stonustoxin; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of several Class I TRIM proteins, including TRIM14, TRIM16 and TRIM25, TRIM47 as well as RING finger protein RNF135 and stonustoxin, a secreted poisonous protein of the stonefish Synanceja horrida. TRIM16 (also known as estrogen-responsive B box protein or EBBP) has E3 ubiquitin ligase activity. It is a regulator of keratinocyte differentiation and a tumor suppressor in retinoid-sensitive neuroblastoma. TRIM25 (also called Efp) ubiquitinates the N terminus of the viral RNA receptor retinoic acid-inducible gene-I (RIG-I) in response to viral infection, leading to activation of the RIG-I signaling pathway, thus resulting in type I interferon production to limit viral replication. It has been shown that the influenza A virus targets TRIM25 and disables its antiviral function. TRIM47, also known as GOA (Gene overexpressed in astrocytoma protein) or RNF100 (RING finger protein 100), is highly expressed in kidney tubular cells, but low expressed in most tissue. It is overexpressed in astrocytoma tumor cells and plays an important role in the process of dedifferentiation that is associated with astrocytoma tumorigenesis. RNF135 ubiquitinates RIG-I (retinoic acid-inducible gene-I) to promote interferon-beta induction during the early phase of viral infection. Stonustoxin (STNX) is a hypotensive and lethal protein factor that also possesses other biological activities such as species-specific hemolysis (due to its ability to form pores in the cell membrane) and platelet aggregation, edema-induction, and endothelium-dependent vasorelaxation (mediated by the nitric oxide pathway and activation of potassium channels). 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 767939046 332 LDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDrATCVLAHTGITGGRHTWVVsiDLAHGGSCTVGVVSEDVQRKG- 410
Cdd:cd12891    3 LDPNTAHNNLALSGDLKTVTCSSENQHYPDSPERFT-HSQVLSTQSFSSGRHYWEV--EVSESGGWSVGVAYPSIERKGd 79

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 411 ELRLRPEEGVWAvrLAW--GFVSALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTnAVTrEPI---YTFTASFTRKVIPF 485
Cdd:cd12891   80 ESRIGRNDKSWC--LEWqdKSFSAWHNNEETPLPSVSSRRLGVYLDYEAGRLSFY-ELS-DPIrhlHTFTATFTEPLHPA 155

                 ....*...
gi 767939046 486 FGLWGRGS 493
Cdd:cd12891  156 FWVLEGGW 163

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 767939046 330 ISLDPQTSHPKLLLSEDHQRAQFSYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVsiDLAHGGSCTVGVVSEDVQRK 409
Cdd:cd15828   12 VTLDPETAHPQLTVSEDRKSVLYGEMKQNVCYNPRRFYLCPAVLGSEGFHSGRQYWEV--EVGDKPEWTLGVCQDCLPRN 89

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 767939046 410 GELRLRPEEGVWAVRL--AWGFVsALGSFPTRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFTASFTRKVIPFF 486
Cdd:cd15828   90 WSNQPSVQDGLWAIGRysESNYV-ALGPKKIQLLPKVRPSKIGIFLDYELGEVSFYNMNDRSLLYTFSDSFTGTLWPYF 167

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 327 PAHISLDPQTSHPKLLLSEDHQRAQF-SYKWQNSPDNPQRFDRATCVLAHTGITGGRHTWVVSIdlAHGGSCTVGVVSED 405
Cdd:cd13744   11 PAALTLDPVTAHQRLILSDDCTIVAYgNLHPQPLQDSPKRFDVEVSVLGSEGFSGGVHYWEVVV--SEKTQWMIGLAHEA 88

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767939046 406 VQRKGELRLRPEEGVWAVRLAWGFVSALGSFP-TRLTLKEQPRQVRVSLDYEVGWVTFTNAVTREPIYTFTASFTRKVIP 484
Cdd:cd13744   89 VSRKGSIQIQPGRGFYCIVMHDGNQYSACTEPwTRLNVKSKLEKVGVYLDYDKGLLIFYNADDMSWLYTFREKFPGKLCS 168

                 ..
gi 767939046 485 FF 486
Cdd:cd13744  169 YF 170