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 998471489   113 KWQYE--LMLGSKGVMQVGWVTSNCKFSQEKGVGDTQDSYAYDGNRVRKWNVSTY-KYGEP-WLAGDVIGCCLDLDEGSV 188
Cdd:pfam00622    1 RHYFEveIFGQDGGGWRVGWATKSVPRKGERFLGDESGSWGYDGWTGKKYWASTSpLTGLPlFEPGDVIGCFLDYEAGTI 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 998471489   189 HFYRNGRSLGVAFDRVRAGPGLvyFPAVSLAFGENLVANFGAT 231
Cdd:pfam00622   81 SFTKNGKSLGYAFRDVPFAGPL--FPAVSLGAGEGLKFNFGLR 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 998471489  112 GKWQYE--LMLGSKGVMQVGWVTSNCKFSQEKGVGDTQDSYAYDGNRVRKWNVST-YKYGEPWLAGDVIGCCLDLDEGSV 188
Cdd:cd11709     1 GKWYWEvrVDSGNGGLIQVGWATKSFSLDGEGGVGDDEESWGYDGSRLRKGHGGSsGPGGRPWKSGDVVGCLLDLDEGTL 80

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 998471489  189 HFYRNGRSLGVAFDRVRAGPGLVYfPAVSLAFGENLVAN 227
Cdd:cd11709    81 SFSLNGKDLGVAFTNLFLKGGGLY-PAVSLGSGQGVTIN 118

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

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 998471489    111 KGKWQYELMLGSKGVMQVGWVTSNCKFSQEKGVGDTQDSYAYDGNRVRKWNVSTYK-YGEPW-LAGDVIGCCLDLDEGSV 188
Cdd:smart00449    1 SGRHYFEVEIGDGGHWRVGVATKSVPRGYFALLGEDKGSWGYDGDGGKKYHNSTGPeYGLPLqEPGDVIGCFLDLEAGTI 80

                            90       100       110       120
                    ....*....|....*....|....*....|....*....|..
gi 998471489    189 HFYRNGRSL-GVAFDRVRAGPGLvyFPAVSLAFGENLVANFG 229
Cdd:smart00449   81 SFYKNGKYLhGLAFFDVKFSGPL--YPAFSLGSGNSVRLNFG 120

SPRY domain 2 (SPRY2) of ryanodine receptor (RyR); This SPRY domain (SPRY2) is the second 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, The SPRY2 domain has been shown to bind to the dihydropryidine receptor (DHPR) II-III loop and the ASI region of RyR1

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 998471489  109 VFKGKWQYELMLGSKGVMQVGWVTSNCKFSQEkgVGDTQDSYAYDGNRVRKWNVSTYKYGEPWLAGDVIGCCLDLDEGSV 188
Cdd:cd12878    11 VTSGKWYFEFEVLTSGYMRVGWARPGFRPDLE--LGSDDLSYAFDGFLARKWHQGSESFGKQWQPGDVVGCMLDLVDRTI 88

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 998471489  189 HFYRNGR----SLG--VAFDRVRAGPGLVyfPAVSLAFGENLVANFG 229
Cdd:cd12878    89 SFTLNGEllidSSGseVAFKDIEIGEGFV--PACSLGVGQKGRLNLG 133

SPRY domain at N-terminus of Really Interesting New Gene (RING) finger domain; This SPRY domain is found at the N-terminus of RING finger domains which are present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. RING-finger domain is a type of Zn-finger that binds two Zn atoms and is identified in proteins with a wide range of functions such as viral replication, signal transduction, and development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 998471489  112 GKWQYELMLGSKGVMQVGWVTSNCKFSQEK--GVGDTQDSYAYDGNRVRKW-NVSTYKYGEP-WLAGDVIGCCLDLDEGS 187
Cdd:cd12883     1 GVWYYEVTVLTSGVMQIGWATKDSKFLNHEgyGIGDDEYSCAYDGCRQLIWyNAKSKPHTHPrWKPGDVLGCLLDLNKKQ 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 998471489  188 VHFYRNG---RSLGVAFDRVRAGpglvYFPAVSLAFGENLVANFG 229
Cdd:cd12883    81 MIFSLNGnrlPPERQVFTSAKSG----FFAAASFMSFQQCEFNFG 121

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 998471489   85 FIVDKDRLGVSSQSN--FNT----IRGTCCVFKGKWQYELMLGSK-------------GVMQVGWVTSNCKFSqekgVGD 145
Cdd:cd12884    12 LKISKDRYSASPLTDegFAYlwagARATYGVTKGKVCFEVKVTENlpvkhlpteetdpHVVRVGWSVDSSSLQ----LGE 87

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 998471489  146 TQDSYAYDGNRvRKW-NVSTYKYGEPWLAGDVIGCCLDLD--EGSVHFYRNGRSLGVAFD-RVRAGPGLVYFPAV 216
Cdd:cd12884    88 EEFSYGYGSTG-KKStNCKFEDYGEPFGENDVIGCYLDFEsePVEISFSKNGKDLGVAFKiSKEELGGKALFPHV 161

SPRY domain-like in bacteria; This family contains SPRY-like domains that are found only in bacterial and are mostly uncharacterized. 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 eukaryotic 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).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 998471489  112 GKWQYELMLGSKGV---MQVGWVTSN-CKFSQEKGVGDTQDSYA---YDGNRVRKWNVSTYkYGEPWLAGDVIGCCLDLD 184
Cdd:cd12886     1 GKWYWEVTVVSSAAstyAGIGVANAAaTGNNGLNGIELSSIGYSlgvYSGNKLSNGSSVAT-YGAGFTAGDVIGVALDLD 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 998471489  185 EGSVHFYRNGRSLGV---AFDRVRAGPGLVYFPAVSL--AFGENLVANFG 229
Cdd:cd12886    80 AGKIWFYKNGVWQGGgdpAPGTNPAFAGTAMYPAVTGgsSTGGSFTANFG 129

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 998471489  164 TYKYGEPW-LAGDVIGCCLDLDEGSVHFYRNGRSLGVAFDRVRAgpGLVYFPAVS 217
Cdd:cd12876   104 SRPYTSPFgNQGTIIGVHLDMWRGTLTFYKNGKPLGVAFTGLNG--VKPLYPMVS 156

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 998471489  143 VGDTQDSYAYDGNRVRKW----NVSTYKY------GEPWLAGDVIGCCLDLDEGSVHFYRNGRSLGVAFdrvRAGPGLVY 212
Cdd:cd12906    80 VGSNEESWGWDIGRNKLYhdskNQPGWTYpaflepDENFVVPDKFLVVLDMDEGTLSFVVDGQYLGVAF---RGLKGKKL 156

                  ....*....
gi 998471489  213 FPAVSLAFG 221
Cdd:cd12906   157 YPIVSAVWG 165

SPRY domain in the F-box family Fbxo45; Fbxo45 is a novel synaptic E3 and ubiquitin ligase, related to the suppressor of cytokine signaling (SOCS) proteins and located N-terminal to a SPRY (SPla and the ryanodine receptor) domain. Fbxo45 induces the degradation of a synaptic vesicle-priming factor, Munc13-1, via the SPRY domain, thus playing an important role in the regulation of neurotransmission by modulating Munc13-1 at the synapse. F-box motifs are found in proteins that function as the substrate recognition component of SCF E3 complexes.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 998471489  144 GDTQDSYAydgnrvRKWNVSTYKYGEPwlagdvIGCCLDLDEGSVHFYRNGRSLGVAFDRVragPGLVYFPAVSLAFG 221
Cdd:cd12907    98 GDSQGNYP------QCNNAPKYQVGER------IRVILDCEDNTLAFERGYEFLGVAFRGL---PPTKLYPAVSAVYG 160