SPRY domain; SPRY domains, first identified in the SP1A kinase of Dictyostelium and rabbit Ryanodine receptor (hence the name), are homologous to B30.2. SPRY domains have been identified in at least 11 protein families, covering a wide range of functions, including regulation of cytokine signaling (SOCS), RNA metabolism (DDX1 and hnRNP), immunity to retroviruses (TRIM5alpha), intracellular calcium release (ryanodine receptors or RyR) and regulatory and developmental processes (HERC1 and Ash2L). B30.2 also contains residues in the N-terminus that form a distinct PRY domain structure; i.e. B30.2 domain consists of PRY and SPRY subdomains. B30.2 domains comprise the C-terminus of three protein families: BTNs (receptor glycoproteins of immunoglobulin superfamily); several TRIM proteins (composed of RING/B-box/coiled-coil or RBCC core); Stonutoxin (secreted poisonous protein of the stonefish Synanceia horrida). TRIM/RBCC proteins are involved in a variety of processes, including apoptosis, cell cycle regulation, cell growth, senescence, viral response, meiosis, cell differentiation, and vesicular transport. Genes belonging to this family are implicated in several human diseases that vary from cancer to rare genetic syndromes. The PRY-SPRY domain in these TRIM families is suggested to serve as the target binding site. While SPRY domains are evolutionarily ancient, B30.2 domains are a more recent adaptation where the SPRY/PRY combination is a possible component of immune defense. Mutations found in the SPRY-containing proteins have shown to cause Mediterranean fever and Opitz syndrome.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274 335 FTTGKHYWELDLKDCEHWAVGVCS-NVwlSRSHKKIGSSGA-FLLVCVKEGNHYSLFTTCPVSHHYIEKPTgRVGVFLDC 412
Cdd:cd13733   50 FSSGRHYWEVEVGGKTDWDLGVAReSV--NRKGKITLSPENgYWTVGLRNGNEYKALTSPSTPLSLREKPQ-KVGVFLDY 126

                         90       100       110
                 ....*....|....*....|....*....|....
gi 219283274 413 EGGCMSFLDVAKSSLIHSYHpEAFSLRVRPFFST 446
Cdd:cd13733  127 EEGQVSFYNVDDGSHIYTFT-DCFTEKLYPYFSP 159

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 219283274  10 QEILTCFICLGIFTDLVLTRCGHPFCRACLLLFSADTQIPIHCPLCRHP 58
Cdd:cd23133    1 EETLTCSICQGIFMNPVYLRCGHKFCEACLLLFQEDIKFPAYCPMCRQP 49

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 219283274 335 FTTGKHYWELDLKDCEHWAVGVCS-NVwlSRSHKKIGSSGA-FLLVCVKEGNHYSLFTTCPVSHHYIEKPTgRVGVFLDC 412
Cdd:cd13733   50 FSSGRHYWEVEVGGKTDWDLGVAReSV--NRKGKITLSPENgYWTVGLRNGNEYKALTSPSTPLSLREKPQ-KVGVFLDY 126

                         90       100       110
                 ....*....|....*....|....*....|....
gi 219283274 413 EGGCMSFLDVAKSSLIHSYHpEAFSLRVRPFFST 446
Cdd:cd13733  127 EEGQVSFYNVDDGSHIYTFT-DCFTEKLYPYFSP 159

RING finger, HC subclass, found in Mus musculus tripartite motif-containing protein 43 (TRIM43) and similar propteins; This subfamily includes TRIM43A, TRIM43B and TRIM43C, which are expressed specifically in mouse preimplantation embryos. They contain a typical C3HC4-type RING-HC finger.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 219283274  10 QEILTCFICLGIFTDLVLTRCGHPFCRACLLLFSADTQIPIHCPLCRHP 58
Cdd:cd23133    1 EETLTCSICQGIFMNPVYLRCGHKFCEACLLLFQEDIKFPAYCPMCRQP 49

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 219283274   338 GKHYWELDLKDCEHWAVGVCSNVWLSRSHKKIGSSGAFLLVCVKEGNHYSLFTTCPVSHHYIEKPTgRVGVFLDCEGGCM 417
Cdd:smart00449   2 GRHYFEVEIGDGGHWRVGVATKSVPRGYFALLGEDKGSWGYDGDGGKKYHNSTGPEYGLPLQEPGD-VIGCFLDLEAGTI 80

                           90       100
                   ....*....|....*....|....*...
gi 219283274   418 SFLDVAKSSLIHSYHPEAFSLRVRPFFS 445
Cdd:smart00449  81 SFYKNGKYLHGLAFFDVKFSGPLYPAFS 108

RING-type zinc-finger; This zinc-finger is a typical RING-type of plant ubiquitin ligases.

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 219283274   15 CFICLGIFTDLVLTrCGHPFCRACLLLFSADTQIPIHCP 53
Cdd:pfam13445   1 CPICLELFTDPVLP-CGHTFCRECLEEMSQKKGGKFKCP 38

B-box zinc finger;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 219283274   87 SEEHKCMTHKERK-TIFCDENRVLLCQLCSKSqEHRGHRHC 126
Cdd:pfam00643   1 SKERLCPEHEEEPlTLYCNDCQELLCEECSVG-EHRGHTVV 40

exonuclease SbcC; All proteins in this family for which functions are known are part of an exonuclease complex with sbcD homologs. This complex is involved in the initiation of recombination to regulate the levels of palindromic sequences in DNA. 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 219283274    63 FRTAIPGKKLISIVRKERIKKY--LSSEEHKcmTHKERKT-IFCDENRVLLCQLCSKSQEHRGHRHCHIEEAVLKQMEKL 139
Cdd:TIGR00618  157 FLKAKSKEKKELLMNLFPLDQYtqLALMEFA--KKKSLHGkAELLTLRSQLLTLCTPCMPDTYHERKQVLEKELKHLREA 234

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274   140 LKQMESLLKKIQELQENLEaEKTMTDQWMDYVTLREEMIRTE---YRKLYPSLDE--------EEAQHIECMKNQGNTNL 208
Cdd:TIGR00618  235 LQQTQQSHAYLTQKREAQE-EQLKKQQLLKQLRARIEELRAQeavLEETQERINRarkaaplaAHIKAVTQIEQQAQRIH 313

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|....*...
gi 219283274   209 EELRKSEAmmvhKRSQLMKVYQELMTMSQKPYEvLQQGLDDLFRRCEL 256
Cdd:TIGR00618  314 TELQSKMR----SRAKLLMKRAAHVKQQSSIEE-QRRLLQTLHSQEIH 356

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 219283274 335 FTTGKHYWELDLKDCEHWAVGVCS-NVwlSRSHKKIGSSGA-FLLVCVKEGNHYSLFTTCPVSHHYIEKPTgRVGVFLDC 412
Cdd:cd13733   50 FSSGRHYWEVEVGGKTDWDLGVAReSV--NRKGKITLSPENgYWTVGLRNGNEYKALTSPSTPLSLREKPQ-KVGVFLDY 126

                         90       100       110
                 ....*....|....*....|....*....|....
gi 219283274 413 EGGCMSFLDVAKSSLIHSYHpEAFSLRVRPFFST 446
Cdd:cd13733  127 EEGQVSFYNVDDGSHIYTFT-DCFTEKLYPYFSP 159

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 219283274 335 FTTGKHYWELDLKDCEHWAVGVCSNVwLSRSHKK--IGSSGAFLLVCVKEgNHYSLFTTCPVSHHYIEKPTgRVGVFLDC 412
Cdd:cd12874   49 FSSGRHYWEVDVQDDSSWYVGVTYKS-LPRKGKMsnLGRNNGSWCLEWRE-NEFSAWHNNPETRLPVTPPR-RLGVFLDC 125

                         90       100       110
                 ....*....|....*....|....*....|....
gi 219283274 413 EGGCMSFLDVAKS-SLIHSYHpEAFSLRVRPFFS 445
Cdd:cd12874  126 DGGSLSFYGVTDGvQLLYTFK-AKFTEPLYPAFW 158

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 219283274 325 SYRASWGAMDFTTGKHYWELDLKDCEHWAVGVCSNVWLSRSHKKIGSSGAFLLVCVKEGNHYSlfTTCPVSHHYIEKPTG 404
Cdd:cd12900   43 NYPMVLGAQRFNSGKHYWEVDVTGKEAWDLGVCRDSVRRKGQFLLSPENGFWTIWLWNKKYEA--GTSPQTTLHLQVPPC 120

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 219283274 405 RVGVFLDCEGGCMSFLDVAK-SSLIHSYHPEAFSLRVRPFFS 445
Cdd:cd12900  121 QVGIFLDYEAGVVSFYNITDhGSLIYTFSECAFTGPLRPFFN 162

Ret finger protein-like (RFPL), includes RFP1, 2, 3, 4; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of RFPL protein family, which includes RFPL1, RFPL2, RFPL3 and RFPL4. In humans, RFPL transcripts can be detected at the onset of neurogenesis in differentiating human embryonic stem cells, and in the developing human neocortex. The human RFPL1, 2, 3 genes have a role in neocortex development. RFPL1 is a primate-specific target gene of Pax6, a key transcription factor for pancreas, eye and neocortex development; human RFPL1 decreases cell number through its RFPL-defining motif (RDM) and SPRY domains. The RFPL4 (also known as RFPL4A) gene encodes a putative E3 ubiquitin-protein ligase expressed in adult germ cells and interacts with oocyte proteins of the ubiquitin-proteasome degradation pathway.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274 305 DIRRFTSRPCHQNtSLDSAGSYRAS---WGAMDFTTGKHYWELDLKDCEHWAVGVC-------SNVWLSRSHkkigssgA 374
Cdd:cd15821   22 DLRSVRCGCFRQN-RKELAERFDDAlcvLGSPRFTSGRHYWEVDVGTSTEWDLGVCresvnrqGPIELSPEH-------G 93

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 219283274 375 FLLVCVKEGNHYSLfTTCPVSHHYIEKPTGRVGVFLDCEGGCMSFLDVAKSSLIHSYHPEAFSLRVRPFFS 445
Cdd:cd15821   94 FWTVSLRDGSVFFA-STVPLTVLWVNPRLHRVGIFLDMEMGTISFYDVSDGSHIFTFTKISAEEPLRPFFA 163

PRY/SPRY domain of tripartite motif-binding protein 11 (TRIM11), also known as RING finger protein 92 (RNF92); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM11, also known as RING finger protein 92 (RNF92) or BIA1. TRIM11 domains are composed of RING/B-box/coiled-coil core and also known as RBCC proteins. It localizes to the nucleus and the cytoplasm; it is overexpressed in high-grade gliomas and promotes proliferation, invasion, migration and glial tumor growth. TRIM11 increases expression of dopamine beta-hydroxylase gene by interacting with the homeodomain transcription factor, PHOX2B, via the B30.2/SPRY domain, thus playing a potential role in the specification of noradrenergic (NA) neuron phenotype. It has also been shown that TRIM11 plays a critical role in the clearance of mutant PHOX2B, which causes congenital central hypoventilation syndrome, via the proteasome. TRIM11 binds a key component of the activator-mediated cofactor complex (ARC105), and destabilizes it, through the ubiquitin-proteasome system; ARC105 mediates chromatin-directed transcription activation and is a key regulatory factor for transforming growth factor beta (TGFbeta) signaling.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274 331 GAMDFTTGKHYWELDLKDCEHWAVGVC-SNVwlSRSHKKIGSSGAFLLVCVKEGNHYSlftTCPVSHHYIEKPTGRVGVF 409
Cdd:cd15811   46 GRERFTSGRHYWEVEVGDRTSWALGVCkENV--NRKEKGELSAGNGFWILVFLGNYYS---SERRTFAPLRDPPRRVGIF 120

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 219283274 410 LDCEGGCMSFLDVAKSSLIHSYHPEAFSLRVRPFFS 445
Cdd:cd15811  121 LDYEAGHLSFYSATDGSLLFIFPETPFSGTLRPLFS 156

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 219283274 308 RFTSRPChqntsldsagsyraSWGAMDFTTGKHYWELDLKDCEHWAVGVC-SNVwlsrsHKK----IGSSGAFLLVCVKE 382
Cdd:cd15819   39 RFDSLPC--------------VLGQEGFTSGRHYWEVEVGDRTSWDLGVCrDNV-----MRKgrvtLSPENGFWAIRLYG 99

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 219283274 383 GNHYSLftTCPVSHHYIEKPTGRVGVFLDCEGGCMSFLDVAKSSLIHSYHPEAFSLRVRPFFS 445
Cdd:cd15819  100 NEYWAL--TSPETPLTLKEPPRRVGIFLDYEAGDVSFYNMTDGSHIYTFPQTAFSGPLRPFFR 160

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 219283274 331 GAMDFTTGKHYWELDLKDCEHWAVGVCSNVWLSRSHKKIGSSGAFLLVCVKEGNHYSLFTTcPVSHHYIEKPTGRVGVFL 410
Cdd:cd15814   48 GSPCFIAGRHYWEVEVGDKAKWTIGVCEDSVCRKGGVTSAPQNGFWAVSLWYGKEYWALTS-PMTALPLRTPLQRVGIFL 126

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 219283274 411 DCEGGCMSFLDVAKSSLIHSYHPEAFSLRVRPFFSTVYT 449
Cdd:cd15814  127 DYDAGEVSFYNVTERCHTFTFSHATFCGPVRPYFSLSYS 165

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 219283274 308 RFTSRPChqntSLDSAGsyraswgamdFTTGKHYWELDLKDCEHWAVGVCS-NV----WLSRSHKkigssGAFLLVCVKE 382
Cdd:cd12888   37 RFDTWPC----VLGCEG----------FTSGRHYWEVEVGDGGGWAVGVAReSVrrkgEISFSPE-----EGIWAVGQWG 97

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 219283274 383 GNHYSLftTCPVSHHYIEKPTGRVGVFLDCEGGCMSFLDVAKSSLIHSYHPEAFS-LRVRPFF 444
Cdd:cd12888   98 GQYWAL--TSPETPLPLSEVPRRIRVYLDYEGGQVAFFDADNEAPIFTFPPASFAgERIFPWF 158

B-box-type 2 zinc finger found in tripartite motif-containing proteins TRIM43, TRIM48, TRIM49, TRIM51, TRIM64, TRIM77 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, TRIM64C, and TRIM77, whose biological functions 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 target proteins of autoantibodies in the sera of patients with these autoimmune disorders. All family members (except for TRIM51) belong to the C-IV subclass of TRIM (tripartite motif) family of proteins that are defined by their N-terminal RBCC (RING, Bbox, and coiled coil) domains, including three consecutive zinc-binding domains, a RING finger, Bbox2, and a coiled coil region, as well as a SPRY/B30.2 domain positioned C-terminal to the RBCC domain. TRIM51 belongs to unclassified TRIM (tripartite motif) family of proteins that do not have RING fingers. The type 2 B-box (Bbox2) zinc finger is characterized by a CHC3H2 zinc-binding consensus motif.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 219283274  86 SSEEHKCMTHKERKTIFCDENRVLLCQLCSKSQEHRGHRHCHIEEAVLKQMEK 138
Cdd:cd19783    1 SSEEQICGTHRETKKLFCEADKSLLCLLCSSSQEHRAHRHYPIEWAAEEHREK 53

PRY/SPRY domain of tripartite motif-binding protein 17 (TRIM17), also known as testis RING finger protein (terf); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM17, also known as RING finger protein 16 (RNF16) or testis RING finger protein (terf). TRIM17 domain is composed of RING/B-box/coiled-coil core and also known as RBCC protein, expressed almost exclusively in the testis. It exhibits E3 ligase activity, causing protein degradation of ZW10 interacting protein (ZWINT), a known component of the kinetochore complex required for the mitotic spindle checkpoint, and negatively regulates proliferation of breast cancer cells. TRIM17 undergoes ubiquitination in COS7 fibroblast-like cells but is inhibited and stabilized by TRIM44.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274 307 RRFTSRPCHQN-TSLDSAGSYRASWGAMDFTTGKHYWE--LDLKDCEHWAVGVC-SNVwlSRSHK--KIGSSGaFLLVCV 380
Cdd:cd15812   21 RRYLSTPPDGTpCSKDRFLAYPCAVGQETFSSGRHYWEvgMNLTGDALWALGVCrDNV--SRKDRvpKSPENG-FWVVQL 97

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 219283274 381 KEGNHYSLFTTCPVSHHYIEKPTgRVGVFLDCEGGCMSFLDVAKSSLIHSYHPEAFSLRVRPFF 444
Cdd:cd15812   98 SKGKKYLSAMSALTPVTLTEPPS-HMGIFLDFEAGEVSFYSVNDGSHLHTYSQAAFPGPLQPFF 160

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 219283274  10 QEILTCFICLGIFTDLVLTRCGHPFCRACLLLFSADTQIPIHCPLCRHPSKP 61
Cdd:cd16590    4 QEELTCPICLDYFQDPVSIECGHNFCRGCLHRNWAPGGGPFPCPECRHPSAP 55

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274 335 FTTGKHYWELDLKDCEHWAVGVCSN--VWLSRSHKKIGSSGAFLLVCVKEGnhYSLFTTCPVSHHYIEKPTGRVGVFLDC 412
Cdd:cd15809   72 FTSGKHYWEVENRDSLEIAVGVCREdvMGITDGSEMSPHVGIWAICWSSAG--YRPLTSSPVSPTKQEPALHRVGVFLDH 149

                         90       100       110
                 ....*....|....*....|....*....|..
gi 219283274 413 EGGCMSFLDVAKSSLIHSYHPeAFSLRVRPFF 444
Cdd:cd15809  150 GAGEVSFYSAVDGVHLHTFSC-PLVSRLRPFF 180

PRY/SPRY domain in tripartite motif-containing protein 34 (TRIM34), also known as RING finger protein 21 (RNF21) or interferon-responsive finger protein (IFP1); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM34, also known as RING finger protein 21 (RNF21) or interferon-responsive finger protein (IFP1). TRIM34 domain is composed of RING/B-box/coiled-coil core and also known as RBCC protein. The TRIM21 cDNA possesses at least three kinds of isoforms, due to alternative splicing, of which only the long and medium forms contain the SPRY domain. It is an interferon-induced protein, predominantly expressed in the testis, kidney, and ovary. The SPRY domain provides the capsid recognition motif that dictates specificity to retroviral restriction. While the PRY-SPRY domain 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 219283274 331 GAMDFTTGKHYWELDLKDCEHWAVGV-C-------SNVWLSRSHKKIGS----SGAFLLVCVKEGNHYSLF----TTCP- 393
Cdd:cd15825   41 GSQYFSSGKHYWEVDVSKKTAWILGVyCrkrsrtfKYVRQGKNHPNVYSryrpQYGYWVIGLQNKSEYYAFedssTSDPk 120

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 219283274 394 VSHHYIEKPTGRVGVFLDCEGGCMSFLDVAK-SSLIHSYHPEAFSLRVRPFFS 445
Cdd:cd15825  121 VLTLSVATPPHRVGVFLDYEAGTVSFFNVTNhGSLIYKFSKCCFSQPVYPYFN 173

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 219283274 335 FTTGKHYWELDLKDCEHWAVGVCSN--------VWLSRSHKKIGssgafLLVCvkeGNHYSlfttcpVSHHYIEKPT--- 403
Cdd:cd12891   48 FSSGRHYWEVEVSESGGWSVGVAYPsierkgdeSRIGRNDKSWC-----LEWQ---DKSFS------AWHNNEETPLpsv 113

                         90       100       110
                 ....*....|....*....|....*....|..
gi 219283274 404 --GRVGVFLDCEGGCMSFLDVAKS-SLIHSYH 432
Cdd:cd12891  114 ssRRLGVYLDYEAGRLSFYELSDPiRHLHTFT 145

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 219283274 335 FTTGKHYWELDLKDCEHWAVGVCSNVwLSRSHK--KIGSSGAFLLVCvKEGNHYSLFT--TCPVSHHYIEKPTgRVGVFL 410
Cdd:cd12897   62 FSEGEHYWEVVVGDKPRWALGVIKGT-ASRKGKlhASPSHGVWLIGL-KEGKVYEAHGepKEPRPLRVAGRPH-RIGVYL 138

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 219283274 411 DCEGGCMSFLDVAKSS---LIHSYHpEAFSLRVRPFFSTVY 448
Cdd:cd12897  139 SFEDGVLSFFDASDPDdlrTLYTFQ-ERFQGKLYPFFDVCW 178

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 219283274  339 KHYWE--LDLKDCEHWAVGVCSNVWLSRSHKKIGSSGAFLLVCVKEGNHYSLFTTCPVSHHYIEKPTgRVGVFLDCEGGC 416
Cdd:pfam00622   1 RHYFEveIFGQDGGGWRVGWATKSVPRKGERFLGDESGSWGYDGWTGKKYWASTSPLTGLPLFEPGD-VIGCFLDYEAGT 79

                          90       100
                  ....*....|....*....|....*....
gi 219283274  417 MSFLDVAKsSLIHSYHPEAFSLRVRPFFS 445
Cdd:pfam00622  80 ISFTKNGK-SLGYAFRDVPFAGPLFPAVS 107

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 219283274 331 GAMDFTTGKHYWELDLKDCEHWAVGVCSNVWLSRSHKKIGSSGAFLLVCVKEGNHYSLFTTCPVSHHYIEKPTgRVGVFL 410
Cdd:cd15818   59 GSEGFTSGKHYWEVEVAKKTKWTLGVVRESINRKGNCPLSPEDGFWLLRLRNQNELKALDVPSFSLTLTSNLN-KVGIYL 137

                         90       100       110
                 ....*....|....*....|....*....|....
gi 219283274 411 DCEGGCMSFLDVAKSSLIHSYhPEAFSLRVRPFF 444
Cdd:cd15818  138 DYEGGQVSFYNANTMSHIYTF-SDTFTEKIYPYF 170

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 219283274 325 SYRASWGAMDFTTGKHYWELDLKDCEHWAVGVCSNVWLsrshKKIGSSGAFLLVCVKEGNHYSLFTTC---PVSHHYIEK 401
Cdd:cd15817   40 VYPAVLGSEGFDSGRHFWEVEVGGKGEWILGVCKDSLP----RNAQDPPSPLGGCWQIGRYMSGYVASgpkTTQLLPVVK 115

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 219283274 402 PTgRVGVFLDCEGGCMSFLDVAKSSLIHSYHpEAFSLRVRPFFST 446
Cdd:cd15817  116 PS-RIGIFLDYELGEVSFYNMNDRSHLYTFT-DTFTGKLIPYFYV 158

PRY/SPRY domain containing protein 4 (SPRYD4); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain and is encoded by the SPRYD4 gene. SPRYD4 (SPRY containing domain 4) is ubiquitously expressed in many human tissues, most strongly in kidney, bladder, brain, thymus and stomach. Subcellular localization demonstrates that SPRYD4 protein is localized in the nucleus when overexpressed in COS-7 green monkey cell. It has remained uncharacterized thus far.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274 336 TTGKHYWELDLKDCEHWAVGVcSNVWLSRShKKIGSSGAFLLVCVKEGNHYSLFT--TCPVSHhyIEKPTgRVGVFLDCE 413
Cdd:cd12903   53 TSGRHYWEVTVKRSQEFRIGV-ADVDMSRD-ECIGTNESSWVFAYAQRKWYAMVAneTVPVPL--VGKPD-RVGLLLDYE 127

                         90       100       110
                 ....*....|....*....|....*....|..
gi 219283274 414 GGCMSFLDVAKSSLIHSYHPEaFSLRVRPFFS 445
Cdd:cd12903  128 AGKLSLVDVEKNSVVHTMSAE-FRGPVVPAFA 158

PRY/SPRY domain in tripartite motif-binding protein 72 (TRIM72); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM72. Muscle-specific TRIM72 (also known as Mitsugumin 53 or 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. TRIM72 interacts with dysferlin, a sarcolemmal protein whose deficiency causes Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B); this coordination plays an important role in the repair of sarcolemma damage.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 219283274 335 FTTGKHYWELDLKDCEHWAVGVCSNVWLSRSHKKIGSSGAFLLVCVKEGNHYSLFTTC--PVSHHYIEKPTgRVGVFLDC 412
Cdd:cd13742   63 FSEGEHYWEVIVGDKPRWALGVISAEAGRKGRLHALPSNGFWLLGCKEGKVYEAHVEHkePRALRVEGRPT-RIGVYLSF 141

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 219283274 413 EGGCMSFLDVAKSS---LIHSYHpEAFSLRVRPFF 444
Cdd:cd13742  142 SDGVLSFYDASDEDnlvQLFAFH-ERFPGPLYPFF 175

RING finger, HC subclass, found in tripartite motif-containing protein TRIM65 and similar proteins; TRIM65 is an E3 ubiquitin-protein ligase that interacts with the innate immune receptor MDA5, enhancing its ability to stimulate interferon-beta signaling. It functions as a potential oncogenic protein that negatively regulates p53 through ubiquitination, providing insight into the development of novel approaches targeting TRIM65 for non-small cell lung carcinoma (NSCLC) treatment, and also overcoming chemotherapy resistance. Moreover, TRIM65 negatively regulates microRNA-driven suppression of mRNA translation by targeting TNRC6 proteins for ubiquitination and degradation. TRIM65 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
                 ....*....|....*....|....*....|....*....|....*....|
gi 219283274  10 QEILTCFICLGIFTDLVLTRCGHPFCRACLLLFSAD-TQIPIHCPLCRHP 58
Cdd:cd16609    1 EEELTCSICLGLYQDPVTLPCQHSFCRACIEDHWRQkDEGSFSCPECRAP 50