SOCS (suppressors of cytokine signaling) box. The SOCS box is found in the C-terminal region of CIS/SOCS family proteins (in combination with a SH2 domain), ASBs (ankyrin repeat-containing proteins with a SOCS box), SSBs (SPRY domain-containing proteins with a SOCS box), and WSBs (WD40 repeat-containing proteins with a SOCS box), as well as, other miscellaneous proteins. The function of the SOCS box is the recruitment of the ubiquitin-transferase system. The SOCS box interacts with Elongins B and C, Cullin-5 or Cullin-2, Rbx-1, and E2. Therefore, SOCS-box-containing proteins probably function as E3 ubiquitin ligases and mediate the degradation of proteins associated through their N-terminal regions.

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 569002152 301 SLQYLCCYRLRQLRpnSGDTLEGLPLPPGLKQVLHNK 337
Cdd:cd03717    5 SLQHLCRFVIRQCT--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 569002152  149 HFWEIKMTSPvYGTDMMVGIGTSDVDLDKYHHtfcslLGRDEDSWGLsytgrcCLGHGWGWQYSRPPRITPLLlagllhh 228
Cdd:pfam00622   2 HYFEVEIFGQ-DGGGWRVGWATKSVPRKGERF-----LGDESGSWGY------DGWTGKKYWASTSPLTGLPL------- 62

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569002152  229 kgdktsfssrFGQGSIIGVHLDTWHGTLTFFKNRKCIGVAATRLQNRR-FYPMVCSTAAKSSM 290
Cdd:pfam00622  63 ----------FEPGDVIGCFLDYEAGTISFTKNGKSLGYAFRDVPFAGpLFPAVSLGAGEGLK 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
                 ....*....|....*....|....*....|....*..
gi 569002152 301 SLQYLCCYRLRQLRpnSGDTLEGLPLPPGLKQVLHNK 337
Cdd:cd03717    5 SLQHLCRFVIRQCT--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 569002152  301 SLQYLCCYRLRQ-LRPNSGDTLEGLPLPPGLKQVLH 335
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 569002152 147 GQHFWEIKMTSPVYGTdMMVGIGTSDVDLDKYHHtfcslLGRDEDSWGLsYTGRCCLGHgwgwqysrppritplllagll 226
Cdd:cd11709    1 GKWYWEVRVDSGNGGL-IQVGWATKSFSLDGEGG-----VGDDEESWGY-DGSRLRKGH--------------------- 52

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 569002152 227 hhKGDKTSFSSRFGQGSIIGVHLDTWHGTLTFFKNRKCIGVAATRLQ--NRRFYPmVCSTAAKSSMKVI 293
Cdd:cd11709   53 --GGSSGPGGRPWKSGDVVGCLLDLDEGTLSFSLNGKDLGVAFTNLFlkGGGLYP-AVSLGSGQGVTIN 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 569002152  149 HFWEIKMTSPvYGTDMMVGIGTSDVDLDKYHHtfcslLGRDEDSWGLsytgrcCLGHGWGWQYSRPPRITPLLlagllhh 228
Cdd:pfam00622   2 HYFEVEIFGQ-DGGGWRVGWATKSVPRKGERF-----LGDESGSWGY------DGWTGKKYWASTSPLTGLPL------- 62

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569002152  229 kgdktsfssrFGQGSIIGVHLDTWHGTLTFFKNRKCIGVAATRLQNRR-FYPMVCSTAAKSSM 290
Cdd:pfam00622  63 ----------FEPGDVIGCFLDYEAGTISFTKNGKSLGYAFRDVPFAGpLFPAVSLGAGEGLK 115

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 569002152 135 TAAIRGTKELGDGQHFWEIKMTSPVYGTDMMVGIGTSDVDLDKYHhtFCSLLGRDEDSWGLSyTGRCCLGH----GWGWQ 210
Cdd:cd12906   31 TDCIRGKVGYSRGLHVWEITWPTRQRGTHAVVGVATKDAPLHCVG--YTSLVGSNEESWGWD-IGRNKLYHdsknQPGWT 107

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569002152 211 YSRppritplllagllhHKGDKTSFS--SRFGqgsiigVHLDTWHGTLTFFKNRKCIGVAATRLQNRRFYPMV 281
Cdd:cd12906  108 YPA--------------FLEPDENFVvpDKFL------VVLDMDEGTLSFVVDGQYLGVAFRGLKGKKLYPIV 160

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
                 ....*....|....*....|....*....|....*..
gi 569002152 301 SLQYLCCYRLRQLRpnSGDTLEGLPLPPGLKQVLHNK 337
Cdd:cd03717    5 SLQHLCRFVIRQCT--RRDLIDQLPLPRRLKDYLKEY 39

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 569002152 118 LSCDNRKVSFHMEYSCGTAAIRGTKE------LGD-----GQHFWEIKMTSpvyGTDMMVGIGTSDVDLDKYhhtfcslL 186
Cdd:cd13734   14 LSNDNLTVEYDPEGSKDQAAVLPRRFtgspavLGDvaissGRHYWEVSVSR---STSYRVGVAYKSAPRDED-------L 83

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569002152 187 GRDEDSWGLSYTGRCCLGHGWGWQYsrPPRITPLLlagllhhkgdktsfssrfgqgSIIGVHLDTWHGTLTFF 259
Cdd:cd13734   84 GKNSTSWCLSRDNNRYTARHDGKVV--DLRVTGHP---------------------ARIGVLLDYDNGTLSFY 133

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 569002152 147 GQHFWEIKMTSPVYGTDMMVGIGTSDVdldkyhhTFCSLLGRDED-SWGLSYTgrcclghgwgwQYSrppritplllaGL 225
Cdd:cd12886    1 GKWYWEVTVVSSAASTYAGIGVANAAA-------TGNNGLNGIELsSIGYSLG-----------VYS-----------GN 51

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 569002152 226 LH-HKGDKTSFSSRFGQGSIIGVHLDTWHGTLTFFKNRKCIGVAA------TRLQNRRFYPMVC 282
Cdd:cd12886   52 KLsNGSSVATYGAGFTAGDVIGVALDLDAGKIWFYKNGVWQGGGDpapgtnPAFAGTAMYPAVT 115

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 569002152 118 LSCDNRKVSFHMEYSCGTAAIRGTKEL---------GDGQHFWEIKMTSPvygtdmMVGIGTSDVDLDKYH---HTFcsL 185
Cdd:cd12896   25 LSRQNRRAKHGRSAARGVPASPGSFELwqvqctqsfQHGHHYWEVEVSSH------SVTLGVTYPGLPRHKqggHKD--N 96

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 569002152 186 LGRDEDSWGLSYTGRCCLGhgwgWQYSRPPRitpllLAGLLHHKgdktsfssrfgqgsiIGVHLDTWHGTLTFF 259
Cdd:cd12896   97 IGRNPCSWGLQIQEDSLQA----WHNGRAQK-----LQGVSYRL---------------LGVDLDLEAGTLTFY 146

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 569002152 133 CGTAAIRGTKelGDGQHFWEIKMTSPvyGTdMMVGIGTSDVDLDkyhhtfcslLGRDEDSWGLSYTGRcclghgwgwqys 212
Cdd:cd12873   28 QGCRATKGVK--GKGKYYYEVTVTDE--GL-CRVGWSTEDASLD---------LGTDKFGFGYGGTGK------------ 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 569002152 213 rppritplllaglLHHKGDKTSFSSRFGQGSIIGVHLDTWHGTLTFFKNRKCIGVAATRLQNRR---FYPMVC 282
Cdd:cd12873   82 -------------KSHGRQFDDYGEPFGLGDVIGCYLDLDNGTISFSKNGKDLGKAFDIPPHLRnsaLFPAVC 141

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 569002152   301 SLQYLCCYRLRQLRpnsgDTLEGLPLPPGLKQVLHNK 337
Cdd:smart00969   2 SLQHLCRLAIRRSL----GGIDKLPLPPRLKDYLLYY 34

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 569002152 224 GLLHHKGDKTS-FSSRFGQGSIIGVHLDTWHGTLTFFKNRKCIGVAATRLQNRRFYPMVCS 283
Cdd:cd12881   88 GNLYHNGEQLLrLSSKFHQGDYITVVLDMEEGTLSFGKNGEEPGVAFEDVDATELYPCVMF 148

suppressors of cytokine signalling; suppressors of cytokine signalling

                           10        20        30
                   ....*....|....*....|....*....|....
gi 569002152   301 SLQYLCCYRLRQLRPNsgDTLEGLPLPPGLKQVL 334
Cdd:smart00253   9 SLQHLCRFTIRRCTRT--DQIKTLPLPPKLKDYL 40