SOCS (suppressors of cytokine signaling) box of SOCS-like proteins. The CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. These intracellular proteins regulate the responses of immune cells to cytokines. Identified as negative regulators of the cytokine-JAK-STAT pathway, they seem to play a role in many immunological and pathological processes. The function of the SOCS box is the recruitment of the ubiquitin-transferase system. Related SOCS boxes are also present in Rab40-like proteins and insect proteins of unknown function that also contain a NEUZ (domain in neuralized proteins) domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 27552770 273 SATSLQYLCCHRLRQLRpdSGDTLEGLPLPPGLKQVLHNK 312
Cdd:cd03717   2 SVRSLQHLCRFVIRQCT--RRDLIDQLPLPRRLKDYLKEY 39

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 27552770   149 HFWEIKMTSPvYGTDMMVGIGTSDVDLDKYRHtfcslLGRDEDSWGLS-YTGLLHH--KGDKTSfSSRFGQGSIIGVHLD 225
Cdd:pfam00622   2 HYFEVEIFGQ-DGGGWRVGWATKSVPRKGERF-----LGDESGSWGYDgWTGKKYWasTSPLTG-LPLFEPGDVIGCFLD 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 27552770   226 TWHGTLTFFKNRKCIGVAATKLQNKR-FYPMVCSTAARSSM 265
Cdd:pfam00622  75 YEAGTISFTKNGKSLGYAFRDVPFAGpLFPAVSLGAGEGLK 115

SOCS (suppressors of cytokine signaling) box of SOCS-like proteins. The CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. These intracellular proteins regulate the responses of immune cells to cytokines. Identified as negative regulators of the cytokine-JAK-STAT pathway, they seem to play a role in many immunological and pathological processes. The function of the SOCS box is the recruitment of the ubiquitin-transferase system. Related SOCS boxes are also present in Rab40-like proteins and insect proteins of unknown function that also contain a NEUZ (domain in neuralized proteins) domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 27552770 273 SATSLQYLCCHRLRQLRpdSGDTLEGLPLPPGLKQVLHNK 312
Cdd:cd03717   2 SVRSLQHLCRFVIRQCT--RRDLIDQLPLPRRLKDYLKEY 39

SOCS box; The SOCS box acts as a bridge between specific substrate- binding domains and more generic proteins that comprise a large family of E3 ubiquitin protein ligases.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 27552770   276 SLQYLCCHRLRQ-LRPDSGDTLEGLPLPPGLKQVLH 310
Cdd:pfam07525   4 SLQHLCRLAIRRaLGKRRLGAIDKLPLPPLLKDYLL 39

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 27552770 147 GQHFWEIKMTSPVYGTdMMVGIGTSDVDLDKYRHtfcslLGRDEDSWGLSYTGLLH-HKGDKTSFSSRFGQGSIIGVHLD 225
Cdd:cd11709   1 GKWYWEVRVDSGNGGL-IQVGWATKSFSLDGEGG-----VGDDEESWGYDGSRLRKgHGGSSGPGGRPWKSGDVVGCLLD 74

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 27552770 226 TWHGTLTFFKNRKCIGVAAT--KLQNKRFYPmVCSTAARSSMKV 267
Cdd:cd11709  75 LDEGTLSFSLNGKDLGVAFTnlFLKGGGLYP-AVSLGSGQGVTI 117

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 27552770   149 HFWEIKMTSPvYGTDMMVGIGTSDVDLDKYRHtfcslLGRDEDSWGLS-YTGLLHH--KGDKTSfSSRFGQGSIIGVHLD 225
Cdd:pfam00622   2 HYFEVEIFGQ-DGGGWRVGWATKSVPRKGERF-----LGDESGSWGYDgWTGKKYWasTSPLTG-LPLFEPGDVIGCFLD 74

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 27552770   226 TWHGTLTFFKNRKCIGVAATKLQNKR-FYPMVCSTAARSSM 265
Cdd:pfam00622  75 YEAGTISFTKNGKSLGYAFRDVPFAGpLFPAVSLGAGEGLK 115

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27552770 135 TAAIRGTKELGEGQHFWEIKMTSPVyGTDMMVGIGTSDVDLdkYRHTFCSLLGRDEDSWGLSYT-GLLHHKGD------K 207
Cdd:cd12907  30 TDGARGKIGFSSGRHAWEVWWEGPL-GTVAVVGIATKHAPL--QCQGYVALLGSDDQSWGWNLVdNHLLHNGDsqgnypQ 106

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|.
gi 27552770 208 TSFSSRFGQGSIIGVHLDTWHGTLTFFKNRKCIGVAATKLQNKRFYPMVCS 258
Cdd:cd12907 107 CNNAPKYQVGERIRVILDCEDNTLAFERGYEFLGVAFRGLPPTKLYPAVSA 157

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 27552770 147 GQHFWEIKMTSPVYGTDMMVGIGTSDVdldkyrhTFCSLLGRDED-SWGLS---YTGLLH-HKGDKTSFSSRFGQGSIIG 221
Cdd:cd12886   1 GKWYWEVTVVSSAASTYAGIGVANAAA-------TGNNGLNGIELsSIGYSlgvYSGNKLsNGSSVATYGAGFTAGDVIG 73

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 27552770 222 VHLDTWHGTLTFFKNRKCIGVAA------TKLQNKRFYPMVC 257
Cdd:cd12886  74 VALDLDAGKIWFYKNGVWQGGGDpapgtnPAFAGTAMYPAVT 115

SPRY domain in Ran binding proteins 9 and 10; This family includes SPRY domain in Ran binding protein (RBP or RanBPM) 9 and 10, and similar proteins. RanBP9 (also known as RanBPM), a binding partner of Ran, is a small Ras-like GTPase that exerts multiple functions via interactions with various proteins. RanBP9 and RanBP10 also 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. SPRY domain of RanBPM forms a complex with CD39, a prototypic member of the NTPDase family, thus down-regulating activity substantially. RanBP10 enhances the transcriptional activity of AR in a ligand-dependent manner and exhibits a protein expression pattern different from RanBPM in various cell lines. RanBP10 is highly expressed in AR-positive prostate cancer LNCaP cells, while RanBPM is abundant in WI-38 and MCF-7 cells.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27552770 136 AAIRGTKEL--GEGQHFWEIKMTSPvyGTDMMVGIG--TSDVDLDKyrhtfcsLLGRDEDSWGlsytgllHHKGDKTSFS 211
Cdd:cd12909  12 AAVRANHPIppQCGIYYFEVKIISK--GRDGYIGIGfsTKDVNLNR-------LPGWEPHSWG-------YHGDDGHSFC 75

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 27552770 212 SR---------FGQGSIIGVHLDTWHGTLTFFKNRKCIGVAATKLQNKRFYPMV 256
Cdd:cd12909  76 SSgtgkpygptFTTGDVIGCGINFRDNTAFYTKNGVNLGIAFRDIKKGNLYPTV 129

SOCS (suppressors of cytokine signaling) box of SOCS-like proteins. The CIS/SOCS family of proteins is characterized by the presence of a C-terminal SOCS box and a central SH2 domain. These intracellular proteins regulate the responses of immune cells to cytokines. Identified as negative regulators of the cytokine-JAK-STAT pathway, they seem to play a role in many immunological and pathological processes. The function of the SOCS box is the recruitment of the ubiquitin-transferase system. Related SOCS boxes are also present in Rab40-like proteins and insect proteins of unknown function that also contain a NEUZ (domain in neuralized proteins) domain.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|
gi 27552770 273 SATSLQYLCCHRLRQLRpdSGDTLEGLPLPPGLKQVLHNK 312
Cdd:cd03717   2 SVRSLQHLCRFVIRQCT--RRDLIDQLPLPRRLKDYLKEY 39

PRY/SPRY domain in tripartite motif-containing domain 65 (TRIM65); This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of TRIM65 proteins (composed of RING/B-box/coiled-coil core and also known as RBCC proteins). The SPRY/PRY combination is a possible component of immune defense. This protein family has not been characterized.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27552770 118 LSCDNRKVSFHMEYSCGTAAIRGTKEL---------GEGQHFWEIKMTSPvygtdmMVGIGTSDVDLDKYR---HTFcsL 185
Cdd:cd12896  25 LSRQNRRAKHGRSAARGVPASPGSFELwqvqctqsfQHGHHYWEVEVSSH------SVTLGVTYPGLPRHKqggHKD--N 96

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 27552770 186 LGRDEDSWGL---SYTGLLHHKGDKTSFSSRFGQgsIIGVHLDTWHGTLTFF 234
Cdd:cd12896  97 IGRNPCSWGLqiqEDSLQAWHNGRAQKLQGVSYR--LLGVDLDLEAGTLTFY 146

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 27552770 109 DLNKSSATL-LSCDNRKVSF---HMEYSCG-----TAAIRGTKELGEGQHFWEIKMTSpvyGTDMMVGIGTSDVDldkyR 179
Cdd:cd12891   4 DPNTAHNNLaLSGDLKTVTCsseNQHYPDSperftHSQVLSTQSFSSGRHYWEVEVSE---SGGWSVGVAYPSIE----R 76

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 27552770 180 HTFCSLLGRDEDSWGLSYTGLLH---HKGDKTSFSSRFGQgsIIGVHLDTWHGTLTFF 234
Cdd:cd12891  77 KGDESRIGRNDKSWCLEWQDKSFsawHNNEETPLPSVSSR--RLGVYLDYEAGRLSFY 132

PRY/SPRY domain in tripartite motif-containing proteins 1, 9, 18, 36, 46, 67,76 (TRIM1, TRIM9, TRIM18, TRIM36, TRIM46, TRIM67, TRIM76); 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 TRIM1, TRIM9, TRIM18, TRIM36, TRIM46, TRIM67 and TRIM76. TRIM1 (also known as MID2) and its close homolog, TRIM18 (also known as MID1), both contain a B30.2-like domain at their C-terminus and a single fibronectin type III (FN3) motif between it and their N-terminal RBCC domain. Their coiled-coil motifs mediate both homo- and heterodimerization, a prerequisite for association of the rapamycin-sensitive PP2A regulatory subunit Alpha 4 with microtubules. Mutations in TRIM18 have shown to cause Opitz syndrome, a disorder causing congenital anomalies such as cleft lip and palate as well as heart defects. TRIM9 is expressed mainly in the cerebral cortex, and functions as an E3 ubiquitin ligase. Its immunoreactivity is severely decreased in affected brain areas in Parkinson's disease and dementia with Lewy bodies, possibly playing an important role in the regulation of neuronal function and participating in pathological process of Lewy body disease through its ligase. TRIM36 interacts with centromere protein-H, one of the kinetochore proteins and possibly associates with chromosome segregation; an excess of TRIM36 may cause chromosomal instability. TRIM46 has not yet been characterized. TRIM67 negatively regulates Ras activity via degradation of 80K-H, leading to neural differentiation, including neuritogenesis. TRIM76 (also known as cardiomyopathy-associated protein 5 or CMYA5) is a muscle-specific member of the TRIM superfamily, but lacks the RING domain. It is possibly involved in protein kinase A signaling as well as vesicular trafficking. It has also been implicated in Duchenne muscular dystrophy and cardiac disease. 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 27552770 118 LSCDNRKVSFHMEYSCGTAAIR-----------GTKELGEGQHFWEIKMTSpvyGTDMMVGIGTSDVDLDKYrhtfcslL 186
Cdd:cd13734  14 LSNDNLTVEYDPEGSKDQAAVLprrftgspavlGDVAISSGRHYWEVSVSR---STSYRVGVAYKSAPRDED-------L 83

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 27552770 187 GRDEDSWGLSYTG----LLHHKGDKTSFSSrfGQGSIIGVHLDTWHGTLTFF 234
Cdd:cd13734  84 GKNSTSWCLSRDNnrytARHDGKVVDLRVT--GHPARIGVLLDYDNGTLSFY 133

SPRY domain in HERC1; This SPRY domain is found in the HERC1, a large protein related to chromosome condensation regulator RCC1. It is widely expressed in many tissues, playing an important role in intracellular membrane trafficking in the cytoplasm as well as Golgi apparatus. HERC1 also interacts with tuberous sclerosis 2 (TSC2, tuberin), which suppresses cell growth, and results in the destabilization of TSC2. However, the biological function of HERC1 has yet to be defined.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27552770 150 FWEIKMTSPVYGTdmMVGIGTSDVDLDKYRHTfcsllgrdEDSWGL-SYTGLLHHKGDKTS-FSSRFGQGSIIGVHLDTW 227
Cdd:cd12881  48 FYLVKENRGNEGT--CVGVSRKPVTDFNYRTS--------SDMWLYrAYNGNLYHNGEQLLrLSSKFHQGDYITVVLDME 117

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
gi 27552770 228 HGTLTFFKNRKCIGVAATKLQNKRFYPMVC--STAARSSMKVTR 269
Cdd:cd12881 118 EGTLSFGKNGEEPGVAFEDVDATELYPCVMfySSGPGEKVKITD 161

PRY/SPRY domain in RING finger protein RNF135; This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C-terminus of the RING finger protein RNF135 (also known as Riplet/RNF135), which ubiquitinates RIG-I (retinoic acid-inducible gene-I) to promote interferon-beta induction during the early phase of viral infection. Normally, RIG-I is activated by TRIM25 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. However, RNF135, consisting of an N-terminal RING finger domain, C-terminal SPRY and PRY motifs and showing sequence similarity to TRIM25, acts as an alternative factor that promotes RIG-I activation independent of TRIM25.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 27552770 141 TKELGEGQHFWEIKMTspvYGTDMMVGIGTSDVDLDKYrhtfcslLGRDEDSWGLSYTGLLH----HKGDKTSFSSrfGQ 216
Cdd:cd12902  45 SQAFSSGQHYWEVDTR---QCSHWAVGVASWEMSRDQM-------LGRTMDSWCIEWKGTGQlsawHMNKETVLGS--DK 112

                        90
                ....*....|....*...
gi 27552770 217 GSIIGVHLDTWHGTLTFF 234
Cdd:cd12902 113 PRVVGIWLDLEEGKLAFY 130

SOCS box; The SOCS box acts as a bridge between specific substrate- binding domains and more generic proteins that comprise a large family of E3 ubiquitin protein ligases.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 27552770   276 SLQYLCCHRLRQ-LRPDSGDTLEGLPLPPGLKQVLH 310
Cdd:pfam07525   4 SLQHLCRLAIRRaLGKRRLGAIDKLPLPPLLKDYLL 39