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 1907201137  134 KWVYEVLISSQ--GLMQIGWCTINCRFNQEEGVGDTHNSYAYDGNRVRK-WNVTTTNYGKA-WAAGDIVSCLIDLDDGTL 209
Cdd:pfam00622    1 RHYFEVEIFGQdgGGWRVGWATKSVPRKGERFLGDESGSWGYDGWTGKKyWASTSPLTGLPlFEPGDVIGCFLDYEAGTI 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 1907201137  210 SFCLNGVSLGTAFENLSRGLGmaYFPAISLSFKESVAFNFGSR 252
Cdd:pfam00622   81 SFTKNGKSLGYAFRDVPFAGP--LFPAVSLGAGEGLKFNFGLR 121

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 1907201137  133 GKWVYEVLI--SSQGLMQIGWCTINCRFNQEEGVGDTHNSYAYDGNRVRKWNVTT-TNYGKAWAAGDIVSCLIDLDDGTL 209
Cdd:cd11709      1 GKWYWEVRVdsGNGGLIQVGWATKSFSLDGEGGVGDDEESWGYDGSRLRKGHGGSsGPGGRPWKSGDVVGCLLDLDEGTL 80

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1907201137  210 SFCLNGVSLGTAFENLSRgLGMAYFPAISLSFKESVAFN 248
Cdd:cd11709     81 SFSLNGKDLGVAFTNLFL-KGGGLYPAVSLGSGQGVTIN 118

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 1907201137  134 KWVYEVLISSQ--GLMQIGWCTINCRFNQEEGVGDTHNSYAYDGNRVRK-WNVTTTNYGKA-WAAGDIVSCLIDLDDGTL 209
Cdd:pfam00622    1 RHYFEVEIFGQdgGGWRVGWATKSVPRKGERFLGDESGSWGYDGWTGKKyWASTSPLTGLPlFEPGDVIGCFLDYEAGTI 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 1907201137  210 SFCLNGVSLGTAFENLSRGLGmaYFPAISLSFKESVAFNFGSR 252
Cdd:pfam00622   81 SFTKNGKSLGYAFRDVPFAGP--LFPAVSLGAGEGLKFNFGLR 121

SPRY domain associated with DEAD box gene DDX1; This SPRY domain is associated with the DEAD box gene, DDX1, an RNA-dependent ATPase involved in HIV-1 Rev function and virus replication. It is suggested that DDX1 acts as a cellular cofactor by promoting oligomerization of Rev on the Rev response element (RRE). DDX1 RNA is overexpressed in breast cancer, data showing a strong and independent association between poor prognosis and deregulation of the DEAD box protein DDX1, thus potentially serving as an effective prognostic biomarker for early recurrence in primary breast cancer. DDX1 also interacts with RelA and enhances nuclear factor kappaB-mediated transcription. DEAD-box proteins are associated with all levels of RNA metabolism and function, and have been implicated in translation initiation, transcription, RNA splicing, ribosome assembly, RNA transport, and RNA decay.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907201137  125 RSTTCVY-KGKWVYEVLISSQGLMQIGWCTINCRFNqeegVGDTHNSYAYDGNRVRKWNVTTTNYGKAWAAGDIVSCLID 203
Cdd:cd12873     31 RATKGVKgKGKYYYEVTVTDEGLCRVGWSTEDASLD----LGTDKFGFGYGGTGKKSHGRQFDDYGEPFGLGDVIGCYLD 106

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 1907201137  204 LDDGTLSFCLNGVSLGTAFENLSRGLGMAYFPAISLSFKEsVAFNFGSRP 253
Cdd:cd12873    107 LDNGTISFSKNGKDLGKAFDIPPHLRNSALFPAVCLKNAE-VEFNFGDKP 155

SPRY domain in Ran binding proteins, SSH4, HECT E3 and SPRYD3; This family includes SPRY domains found in Ran binding proteins (RBP or RanBPM) 9 and 10, SSH4 (suppressor of SHR3 null mutation protein 4), SPRY domain-containing protein 3 (SPRYD3) as well as HECT, a C-terminal catalytic domain of a subclass of ubiquitin-protein ligase (E3). RanBP9 and RanBP10 act as androgen receptor (AR) coactivators. Both consist of the N-terminal proline- and glutamine-rich regions, the SPRY domain, and LisH-CTLH and CRA motifs. The SPRY domain in SSH4 may be involved in cargo recognition, either directly or by combination with other adaptors, possibly leading to a higher selectivity. SPRYD3 is highly expressed in most tissues in humans, possibly involved in important cellular processes. HECT E3 mediates the direct transfer of ubiquitin from E2 to substrate.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907201137  122 GTIRSTTCVYKGKWVY--EVLI---SSQGLMQIGWCTINCRFNQeeGVGDTHNSYAYDGN--RVRKWNVTTTNYGKAWAA 194
Cdd:cd12885      1 GSVRADHPIPPKVPVFyfEVTIldlGEKGIVSIGFCTSGFPLNR--MPGWEDGSYGYHGDdgRVYLGGGEGENYGPPFGT 78

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1907201137  195 GDIVSCLIDLDDGTLSFCLNGVSLGTAFENLSRGLgmaYFPAISLSFK-ESVAFNFG 250
Cdd:cd12885     79 GDVVGCGINFKTGEVFFTKNGELLGTAFENVVKGR---LYPTVGLGSPgVKVRVNFG 132

SPRY domain in heterogeneous nuclear ribonucleoprotein U-like (hnRNP) protein 1; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of heterogeneous nuclear ribonucleoprotein U-like (hnRNP) protein 1 (also known as HNRPUL1 ) which is a major constituent of nuclear matrix or scaffold and binds directly to DNA sequences through the N-terminal acidic region named serum amyloid P (SAP). Its function is specifically modulated by E1B-55kDa in adenovirus-infected cells. HNRPUL1 also participates in ATR protein kinase signaling pathways during adenovirus infection. Two transcript variants encoding different isoforms have been found for this gene. When associated with bromodomain-containing protein 7 (BRD7), it activates transcription of glucocorticoid-responsive promoter in the absence of ligand-stimulation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907201137  124 IRSTTCVYKGKWVYEVLISS-------------QGLMQIGWCTINCRFNqeegVGDTHNSYAYDGNRvRKW-NVTTTNYG 189
Cdd:cd12884     36 ARATYGVTKGKVCFEVKVTEnlpvkhlpteetdPHVVRVGWSVDSSSLQ----LGEEEFSYGYGSTG-KKStNCKFEDYG 110

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1907201137  190 KAWAAGDIVSCLIDLD--DGTLSFCLNGVSLGTAFEnLSRGL--GMAYFPAIsLSFKESVAFNFGSRP 253
Cdd:cd12884    111 EPFGENDVIGCYLDFEsePVEISFSKNGKDLGVAFK-ISKEElgGKALFPHV-LTKNCAVEVNFGQKE 176

SPRY domain 1 (SPRY1) of ryanodine receptor (RyR); This SPRY domain is the first of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, but no specific function has been found for this first SPRY domain of the RyRs.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907201137  121 FGTIRSTTcVYKgKWVYEVLISSQGLM-------QIGWCTiNCRFNQEE---------GVGDTHNSYAYDGNRV---RKW 181
Cdd:cd12877      8 VGVVEGSA-QYK-KWYFEVEVDHVEQFthqpahlRVGWAN-TSGYVPYPgggegwggnGVGDDLYSYGFDGLHLwtgGRS 84

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1907201137  182 NVTTTNYGKAWAAGDIVSCLIDLDDGTLSFCLNGVSLGTAFENLSrgLGMAYFPAISLSFKESVAFNFG 250
Cdd:cd12877     85 RRVTSGTQHLLKKGDVVGCCLDLSVPSISFRVNGRPVQGMFENFN--LDGMFFPVMSFSAGVSCRFLLG 151

SPRY domain in the suppressor of cytokine signaling 1, 2, 4 families (SOCS1, SOCS2, SOCS4); The SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) is composed of a central SPRY protein interaction domain and a C-terminal SOCS box. All four SPSB proteins interact with c-Met, the hepatocyte growth factor receptor, but only SPSB1, SPSB2, and SPSB4 interact with prostate apoptosis response protein 4 (Par-4). They are negative regulators that recruit the ECS E3 ubiquitin ligase complex to polyubiquitinate inducible nitric-oxide synthase (iNOS), resulting in its proteasomal degradation, thus contributing to protection against the cytotoxic effect of iNOS in activated macrophages. It has been shown that SPSB1 and SPSB4 induce the degradation of iNOS more strongly than SPSB2. The Drosophila melanogaster SPSB1 homolog, GUSTAVUS, interacts with the DEAD box RNA helicase Vasa. Suppressor of cytokine signaling (SOCS) proteins negatively regulate signaling from JAK-associated cytokine receptor complexes, and play key roles in the regulation of immune homeostasis.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907201137  149 IGWCTINCRFnQEEG----VGDTHNSYAYDGNRVR-------KWNVTTTNY---GKAWAAGDIVSCLIDLDDGTLSFCLN 214
Cdd:cd12906     62 VGVATKDAPL-HCVGytslVGSNEESWGWDIGRNKlyhdsknQPGWTYPAFlepDENFVVPDKFLVVLDMDEGTLSFVVD 140

                           90       100
                   ....*....|....*....|....*
gi 1907201137  215 GVSLGTAFenlsRGL-GMAYFPAIS 238
Cdd:cd12906    141 GQYLGVAF----RGLkGKKLYPIVS 161

SPRY domain in the suppressor of cytokine signaling 3 (SOCS3) family; The SPRY domain-containing SOCS box protein family (SPSB1-4, also known as SSB-1 to -4) is composed of a central SPRY protein interaction domain and a C-terminal SOCS box. All four SPSB proteins interact with c-Met, the hepatocyte growth factor receptor, but SOCS3 regulates cellular response to a variety of cytokines such as leukemia inhibitory factor (LIF) and interleukin 6. SOCS3, along with SOCS1, are expressed by immune cells and cells of the central nervous system (CNS) and have the potential to impact immune processes within the CNS. In non-small cell lung cancer (NSCLC), SOCS3 is silenced and proline-rich tyrosine kinase 2 (Pyk2) is over-expressed; it has been suggested that SOCS3 could be an effective way to prevent the progression of NSCLC due to its role in regulating Pyk2 expression.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1907201137  185 TTNYG-KAWAAGDIVSCLIDLDDGTLSFCLNGVSLGTAFENLSRGLGmaYFPAIS 238
Cdd:cd12876    104 SRPYTsPFGNQGTIIGVHLDMWRGTLTFYKNGKPLGVAFTGLNGVKP--LYPMVS 156

SPRY domain 3 (SPRY3) of ryanodine receptor (RyR); This SPRY domain (SPRY3) is the third of three structural repeats in all three isoforms of the ryanodine receptor (RyR), which are the major Ca2+ release channels in the membranes of sarcoplasmic reticulum (SR). There are three RyR genes in mammals; the skeletal RyR1, the cardiac RyR2 and the brain RyR3. The three SPRY domains are located in the N-terminal part of the cytoplasmic region of the RyRs, but no specific function has been found for this third SPRY domain of the RyRs.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907201137  182 NVTTTNYGKAWAAGDIVSCLIDLDDGTLSFCLNGVSLGTAF--ENlsrglGMAYFPAISL--SFKESVAFNFG 250
Cdd:cd12879     84 AEVGQDSSGRASQGLLIGCLIDTATGLLTFTANGKETSTRFqvEP-----GTKLFPAVFVrpTSKEVLQFELG 151