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        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 18203572   9 SLADEVNCPICQGTLREPVTIDCGHNFCRGCLTRYCEIPGPESEESLSCPLCKEPFRPGSF 69
Cdd:cd16593   1 SLADEVNCPICQGTLREPVTIDCGHNFCRACLTRYCEIPGPDLEEPPTCPLCKEPFRPGEF 61

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        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 18203572   9 SLADEVNCPICQGTLREPVTIDCGHNFCRGCLTRYCEIPGPESEESLSCPLCKEPFRPGSF 69
Cdd:cd16593   1 SLADEVNCPICQGTLREPVTIDCGHNFCRACLTRYCEIPGPDLEEPPTCPLCKEPFRPGEF 61

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 18203572    363 GRHTWMVNVDlaHGGSCTVGVVREDVRRKGELRLRPEEGIWAVRLAWGFVSALGSFP-TRLALEEQPRKVQVSLDYEVGW 441
Cdd:smart00449   2 GRHYFEVEIG--DGGHWRVGVATKSVPRGYFALLGEDKGSWGYDGDGGKKYHNSTGPeYGLPLQEPGDVIGCFLDLEAGT 79

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 18203572    442 ITFVNAVTQEHIYTF-TASFTQKIFPLFGLWGRGS 475
Cdd:smart00449  80 ISFYKNGKYLHGLAFfDVKFSGPLYPAFSLGSGNS 114

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 18203572    16 CPICQGTLREPVTIDCGHNFCRGCLTRYCEIPgpeSEESLSCPLC 60
Cdd:pfam15227   1 CPICLDYLEKPVSIECGHSFCLSCINSLQKEP---DGESLLCPQC 42

RING-finger-containing E3 ubiquitin ligase [Signal transduction mechanisms];

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572   3 SAPSVTSLADEVNCPICQGTLREPVTIDCGHNFCRGCLTRYCeipgpesEESLSCPLCKEPFRPGSFRPNWQLANVVENI 82
Cdd:COG5432  15 KIPSLKGLDSMLRCRICDCRISIPCETTCGHTFCSLCIRRHL-------GTQPFCPVCREDPCESRLRGSSGSREINESH 87

                        90
                ....*....|....*...
gi 18203572  83 ERLQLASTRGLEVEDACP 100
Cdd:COG5432  88 ARNRDLLRKVLESLCRLP 105

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 18203572     16 CPICQGT-LREPVTIDCGHNFCRGCLTRYCEipgpesEESLSCPLC 60
Cdd:smart00184   1 CPICLEEyLKDPVILPCGHTFCRSCIRKWLE------SGNNTCPIC 40

E3 ubiquitin-protein ligase RMA2; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 18203572    8 TSLAD---EVNCPICQGTLREPVTIDCGHNFCRGCLTRYCEIPGPESE---------ESLSCPLCKEPFRPGSFRP 71
Cdd:PLN03208  10 TTLVDsggDFDCNICLDQVRDPVVTLCGHLFCWPCIHKWTYASNNSRQrvdqydhkrEPPKCPVCKSDVSEATLVP 85

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 18203572 311 HISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVDLahGGSCTVGVVREDVRR 390
Cdd:cd12888   1 NVTLDPDTAHPRLVLSEDRKSVRWGDTRQDLPDNPERFDTWPCVLGCEGFTSGRHYWEVEVGD--GGGWAVGVARESVRR 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 391 KGELRLRPEEGIWAVRLAWGFVSALGSFPTRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFTASF--TQKIFPLF 468
Cdd:cd12888  79 KGEISFSPEEGIWAVGQWGGQYWALTSPETPLPLSEVPRRIRVYLDYEGGQVAFFDADNEAPIFTFPPASfaGERIFPWF 158

                       170
                ....*....|..
gi 18203572 469 GLWgRGSSFSLS 480
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 18203572 312 ISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVdlahGG--SCTVGVVREDVR 389
Cdd:cd13733   2 VTLDPDTAHPNLILSEDLKSVRYGDKRQNLPDNPERFDTCVCVLGSEGFSSGRHYWEVEV----GGktDWDLGVARESVN 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 390 RKGELRLRPEEGIWAVRLAWGFV-SALGSFPTRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFTASFTQKIFPLF 468
Cdd:cd13733  78 RKGKITLSPENGYWTVGLRNGNEyKALTSPSTPLSLREKPQKVGVFLDYEEGQVSFYNVDDGSHIYTFTDCFTEKLYPYF 157

                ....*
gi 18203572 469 GLWGR 473
Cdd:cd13733 158 SPCLN 162

PRY/SPRY domain in tripartite motif-binding protein 39 (TRIM39) and TRIM39-like; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of pyrin, several tripartite motif-containing proteins (TRIMs), including E3 ubiquitin-protein ligase (TRIM21), RET finger protein (RFP)/tripartite motif protein 27 (TRIM27), as well as butyrophilin (Btns) and butyrophilin-like (Btnl) family members, with the exception of Btnl2. Btn and Btnl family members are novel regulators of immune responses, with many of the genes located within the MHC. They are implicated in T-cell inhibition and modulation of epithelial cell-T cell interactions. TRIM21 (also known as RO52, SSA1 or RNF81) is a major autoantigen in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sjorgen's syndrome. TRIM27 (also known as Ret finger protein, RFP or RNF76) negatively regulates CD4 T-cells by ubiquitinating and inhibiting the class II phosphatidylinositol 3 kinase C2beta (PI3K-C2beta), a kinase critical for KCa3.1 channel activation. The PRY/SPRY domain of Pyrin, which is mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 312 ISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNV-DLAHggsCTVGVVREDVRR 390
Cdd:cd13745   5 VTLDPDTAHPNLVLSEDRKSVRHGDTRQDLPDNPERFDTYPCVLGAEGFTGGRHYWEVEVgDKTE---WTLGVCRESVSR 81

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 18203572 391 KGELRLRPEEGIWAVRLAWGFVSALGSFPTRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFTASFTQKIFPLF 468
Cdd:cd13745  82 KGEVTLSPENGYWTVWLRDGKYEALTSPPTPLPVSVRPSRVGIFLDYEAGEVSFYNVTDRSHLFTFTDTFSGTLRPYF 159

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 18203572 312 ISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVdlAHGGSCTVGVVREDVRRK 391
Cdd:cd15818  15 ITLDPKTAHPNLILSEDLTCVWHGDTKQMLPDNPERFDSSVAVLGSEGFTSGKHYWEVEV--AKKTKWTLGVVRESINRK 92

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 18203572 392 GELRLRPEEGIWAVRLAWGF-VSALGSFPTRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFTASFTQKIFPLF 468
Cdd:cd15818  93 GNCPLSPEDGFWLLRLRNQNeLKALDVPSFSLTLTSNLNKVGIYLDYEGGQVSFYNANTMSHIYTFSDTFTEKIYPYF 170

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 18203572 307 YEPAHISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVdlAHGGSCTVGVVRE 386
Cdd:cd15820   1 FQPADVILDPDTANPILLISEDQRSLQWADEPQNLPDNPKRFDWHYCVLGCKSFTSGRHFWEVEV--GDRKEWYVGVCRE 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 387 DVRRKGELRLRPEEGIWAVRLAWGF-VSALGSFPTRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFT-ASFTQKI 464
Cdd:cd15820  79 NVERKLWVKMAPENGFWTIGLSDGNdYQALTDPRTKLTIANPPQRVGVFLDYETGEVSFYNAMDGSHIYTFPhTSFSGPL 158

                ....
gi 18203572 465 FPLF 468
Cdd:cd15820 159 YPVF 162

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 18203572 283 FPQQAIPLRQEMKTFLEKlcfeldyepahISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTG 362
Cdd:cd15829   3 FPPQYSALQKIIKKFRVD-----------VTLDPETAHPNLLVSEDKKCVTFTKKKQRVPDSPKRFTVNPVVLGFPGFHS 71

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 363 GRHTWMVNVDlaHGGSCTVGVVREDVRRKGELRLRPEEGIWAVRLAWGFVSALGSFPTRLALEEQPRKVQVSLDYEVGWI 442
Cdd:cd15829  72 GRHFWEVEVG--DKPEWAVGVCKDSLSTKARRPPSGQQGCWRIQLQGGDYDAPGAVPPPLLLEVKPRGIGVFLDYELGEI 149

                       170       180       190
                ....*....|....*....|....*....|...
gi 18203572 443 TFVNAVTQEHIYTFTASFTQKIFPLFGLwGRGS 475
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 18203572 312 ISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWmvNVDLAHGGSCTVGVVREDVRRK 391
Cdd:cd15815  15 VTLDPDTAHPELTLSKDQRQVTYGRCQENLDASPKRFTVLPCVLGCEGFTSGRHYF--EVDVGEGTGWDVGVCLENVQRG 92

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 392 GELRLRPEEGIWAVRLAW--GFVsALGSFPTRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTF-TASFTQKIFPLF 468
Cdd:cd15815  93 FGMKQEPEFGFWTIRLCEedGYV-ALTSPPTPLPLREKPLVVGVFLDYEAGLVSFYNMTTGSHIFTFpKASFSDTLRPYF 171

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 18203572 311 HISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVdlahGGSCT--VGVVREDV 388
Cdd:cd15821   5 DMTLDVDTANNYLIISEDLRSVRCGCFRQNRKELAERFDDALCVLGSPRFTSGRHYWEVDV----GTSTEwdLGVCRESV 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 18203572 389 RRKGELRLRPEEGIWAVRL-AWGFVSALGSFPTRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFTASFTQ 462
Cdd:cd15821  81 NRQGPIELSPEHGFWTVSLrDGSVFFASTVPLTVLWVNPRLHRVGIFLDMEMGTISFYDVSDGSHIFTFTKISAE 155

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 18203572 312 ISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVDLAHGGSctVGVVREDVRRK 391
Cdd:cd13741   2 LTLDPDTAHPALLLSPDRRGVRLAERRQEVPEHPKRFSADCCVLGAQGFRSGRHYWEVEVGGRRGWA--VGAARESTHHK 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 392 GEL----------------------RLRPEEG------IWAVRLAWGFVSALGSFP-TRLALEEQPRKVQVSLDYEVGWI 442
Cdd:cd13741  80 EKVgsggssvssgdasssrhhhrrrRLHLPQQpllqreVWCVGTNGKRYQAQSSTEqTLLSPSEKPRRFGVYLDYEAGRL 159

                       170       180       190
                ....*....|....*....|....*....|....*...
gi 18203572 443 TFVNAVTQEHIYTFTASF-TQKIFPLFGLWGRGSSFSL 479
Cdd:cd13741 160 GFYNAETLAHVHTFSAAFlGERVFPFFRVLSKGTRIKL 197

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 18203572 309 PAHISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVdlahgGSCT---VGVVR 385
Cdd:cd12905   3 PAPLTFDPETAHPSLILSRDLTAVTESDEMQPYPRSPKRFLQCVNVLASQGFQSGRHYWEVWV-----GSKTkwdLGVAS 77

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 386 EDVRRKGELRLRPEEGIWAVRLAWGFVSALGSFP-TRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFTASFTQKI 464
Cdd:cd12905  78 ESVDRQARVKLCPENGYWTLRLRNGDEYWAGTQPwTRLRVTSRPQRIGVFLDCEERKVSFYNADDMSLLYSFHQGPRGKV 157

                ....
gi 18203572 465 FPLF 468
Cdd:cd12905 158 FPFF 161

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 18203572   364 RHTWMVNVDLAHGGSCTVGVVREDVRRKGELRLRPEEGIWAVRLAWG-FVSALGSFPTRLALEEQPRKVQVSLDYEVGWI 442
Cdd:pfam00622   1 RHYFEVEIFGQDGGGWRVGWATKSVPRKGERFLGDESGSWGYDGWTGkKYWASTSPLTGLPLFEPGDVIGCFLDYEAGTI 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 18203572   443 TFVNAvTQEHIYTFT-ASFTQKIFPLFGL-WGRGSSFSLSCQ 482
Cdd:pfam00622  81 SFTKN-GKSLGYAFRdVPFAGPLFPAVSLgAGEGLKFNFGLR 121

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 18203572 311 HISLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWmvNVDLAHGGSCTVGVVREDVRR 390
Cdd:cd12900   4 HITLDPDTANPWLILSKDRRQVRLGDTHQNVPENEERFDNYPMVLGAQRFNSGKHYW--EVDVTGKEAWDLGVCRDSVRR 81

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 391 KGELRLRPEEGIWAVRLaWGFVSALGSFP-TRLALEEQPRKVQVSLDYEVGWITFVNAVTQEH-IYTFT-ASFTQKIFPL 467
Cdd:cd12900  82 KGQFLLSPENGFWTIWL-WNKKYEAGTSPqTTLHLQVPPCQVGIFLDYEAGVVSFYNITDHGSlIYTFSeCAFTGPLRPF 160

                .
gi 18203572 468 F 468
Cdd:cd12900 161 F 161

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 18203572 314 LDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDrvTC-VLAQCGFTGGRHTWmvNVDLAHGGSCTVGVVREDVRRKG 392
Cdd:cd12891   3 LDPNTAHNNLALSGDLKTVTCSSENQHYPDSPERFT--HSqVLSTQSFSSGRHYW--EVEVSESGGWSVGVAYPSIERKG 78

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 393 elrlrPEEGI------WAvrLAW--GFVSALGSFPTRLALEEQPRKVQVSLDYEVGWITFVnAVTQ--EHIYTFTASFTQ 462
Cdd:cd12891  79 -----DESRIgrndksWC--LEWqdKSFSAWHNNEETPLPSVSSRRLGVYLDYEAGRLSFY-ELSDpiRHLHTFTATFTE 150

                       170
                ....*....|...
gi 18203572 463 KIFPLFGLWGRGS 475
Cdd:cd12891 151 PLHPAFWVLEGGW 163

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 18203572 309 PAHISLDPQTSHPKLLLSEDHRRARF-SYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWMVNVdlAHGGSCTVGVVRED 387
Cdd:cd13744  11 PAALTLDPVTAHQRLILSDDCTIVAYgNLHPQPLQDSPKRFDVEVSVLGSEGFSGGVHYWEVVV--SEKTQWMIGLAHEA 88

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 388 VRRKGELRLRPEEGIWAVRLAWGFVSALGSFP-TRLALEEQPRKVQVSLDYEVGWITFVNAVTQEHIYTFTASFTQKIFP 466
Cdd:cd13744  89 VSRKGSIQIQPGRGFYCIVMHDGNQYSACTEPwTRLNVKSKLEKVGVYLDYDKGLLIFYNADDMSWLYTFREKFPGKLCS 168

                ..
gi 18203572 467 LF 468
Cdd:cd13744 169 YF 170

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 313 SLDPQTSHPKLLLSEDHRRARFSYKWQNSPDTPQRFDRVTCVLAQCGFTGGRHTWmvNVDLAHGGS-CTVGVVREDVRRK 391
Cdd:cd13738   2 TLEPDTLHPRLRLSDDRLTVSCGWLGTLGLCPPQRFDKLWQVLSRDSFFSGRHYW--EVDLQEAGAgWWVGAAYPSIGRK 79

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 18203572 392 GEL---RLRPEEGIWAVRL----AWGFVSALgsfPTRLALEEQPRKVQVSLDYEVGWITFVNAVT-QEHIYTFTASFTQK 463
Cdd:cd13738  80 GDSeaaRLGWNRQSWCLKRydleYWAFHDGQ---RSRLRPEDDPDRLGVFLDYEAGILSFYDVTGgMTHLHTFRATFQEP 156