ID SPSB4_HUMAN Reviewed; 273 AA. AC Q96A44; DT 30-MAY-2006, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-2001, sequence version 1. DT 02-JUN-2021, entry version 151. DE RecName: Full=SPRY domain-containing SOCS box protein 4; DE Short=SSB-4; GN Name=SPSB4; Synonyms=SSB4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RA Friedel E.J., Nicholson S.E., Nicola N.A., Kile B.T., Hilton D.J.; RT "SOCS box proteins."; RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP FUNCTION IN AN E3 UBIQUITIN-PROTEIN LIGASE COMPLEX, AND INTERACTION WITH RP CUL5; RNF7; ELOB AND ELOC. RX PubMed=15601820; DOI=10.1101/gad.1252404; RA Kamura T., Maenaka K., Kotoshiba S., Matsumoto M., Kohda D., Conaway R.C., RA Conaway J.W., Nakayama K.I.; RT "VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 RT and Cul5-Rbx2 modules of ubiquitin ligases."; RL Genes Dev. 18:3055-3065(2004). RN [5] RP INTERACTION WITH MET. RX PubMed=15713673; DOI=10.1074/jbc.m413897200; RA Wang D., Li Z., Messing E.M., Wu G.; RT "The SPRY domain-containing SOCS box protein 1 (SSB-1) interacts with MET RT and enhances the hepatocyte growth factor-induced Erk-Elk-1-serum response RT element pathway."; RL J. Biol. Chem. 280:16393-16401(2005). RN [6] RP FUNCTION, INTERACTION WITH NOS2, SUBCELLULAR LOCATION, AND DOMAIN SOCS BOX. RX PubMed=21199876; DOI=10.1074/jbc.m110.190678; RA Nishiya T., Matsumoto K., Maekawa S., Kajita E., Horinouchi T., RA Fujimuro M., Ogasawara K., Uehara T., Miwa S.; RT "Regulation of inducible nitric-oxide synthase by the SPRY domain- and SOCS RT box-containing proteins."; RL J. Biol. Chem. 286:9009-9019(2011). RN [7] RP FUNCTION. RX PubMed=26392558; DOI=10.1073/pnas.1501204112; RA DeBruyne J.P., Baggs J.E., Sato T.K., Hogenesch J.B.; RT "Ubiquitin ligase Siah2 regulates RevErbalpha degradation and the mammalian RT circadian clock."; RL Proc. Natl. Acad. Sci. U.S.A. 112:12420-12425(2015). RN [8] RP FUNCTION, AND INTERACTION WITH EPHB2. RX PubMed=28931592; DOI=10.1091/mbc.e17-07-0450; RA Okumura F., Joo-Okumura A., Obara K., Petersen A., Nishikimi A., Fukui Y., RA Nakatsukasa K., Kamura T.; RT "Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated by RT EphB2."; RL Mol. Biol. Cell 28:3532-3541(2017). RN [9] {ECO:0007744|PDB:2V24} RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 28-233, AND INTERACTION WITH RP PAWR. RX PubMed=20561531; DOI=10.1016/j.jmb.2010.06.017; RA Filippakopoulos P., Low A., Sharpe T.D., Uppenberg J., Yao S., Kuang Z., RA Savitsky P., Lewis R.S., Nicholson S.E., Norton R.S., Bullock A.N.; RT "Structural basis for Par-4 recognition by the SPRY domain- and SOCS box- RT containing proteins SPSB1, SPSB2, and SPSB4."; RL J. Mol. Biol. 401:389-402(2010). CC -!- FUNCTION: Substrate recognition component of a SCF-like ECS (Elongin CC BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which CC mediates the ubiquitination and subsequent proteasomal degradation of CC target proteins (PubMed:21199876, PubMed:15601820). Negatively CC regulates nitric oxide (NO) production and limits cellular toxicity in CC activated macrophages by mediating the ubiquitination and proteasomal CC degradation of NOS2 (PubMed:21199876). Acts as a bridge which links CC NOS2 with the ECS E3 ubiquitin ligase complex components ELOC and CUL5 CC (PubMed:21199876). Diminishes EphB2-dependent cell repulsive responses CC by mediating the ubiquitination and degradation of EphB2/CTF2 CC (PubMed:28931592). Regulates cellular clock function by mediating the CC ubiquitin/proteasome-dependent degradation of the circadian CC transcriptional repressor NR1D1 (PubMed:26392558). CC {ECO:0000269|PubMed:15601820, ECO:0000269|PubMed:21199876, CC ECO:0000269|PubMed:26392558, ECO:0000269|PubMed:28931592}. CC -!- PATHWAY: Protein modification; protein ubiquitination. CC -!- SUBUNIT: Component of the probable ECS(SPSB4) E3 ubiquitin-protein CC ligase complex which contains CUL5, RNF7/RBX2, Elongin BC complex and CC SPSB4 (PubMed:15601820). Interacts with CUL5; RNF7; ELOB and ELOC CC (PubMed:15601820). Interacts with MET (PubMed:15713673). Interacts (via CC B30.2/SPRY domain) with PAWR; this interaction occurs in association CC with the Elongin BC complex (PubMed:20561531). Interacts with NOS2 CC (PubMed:21199876). Interacts with EPHB2 (PubMed:28931592). CC {ECO:0000269|PubMed:15601820, ECO:0000269|PubMed:15713673, CC ECO:0000269|PubMed:20561531, ECO:0000269|PubMed:21199876, CC ECO:0000269|PubMed:28931592}. CC -!- INTERACTION: CC Q96A44; Q15369: ELOC; NbExp=2; IntAct=EBI-2323233, EBI-301231; CC Q96A44; P40337-2: VHL; NbExp=3; IntAct=EBI-2323233, EBI-12157263; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305}. Cytoplasm, cytosol CC {ECO:0000269|PubMed:21199876}. Note=Exhibits a diffuse cytosolic CC localization. {ECO:0000269|PubMed:21199876}. CC -!- DOMAIN: The SOCS box domain mediates the interaction with the Elongin CC BC complex, an adapter module in different E3 ubiquitin ligase CC complexes (By similarity). Essential for its ability to link NOS2 and CC the ECS E3 ubiquitin ligase complex components ELOC and CUL5 CC (PubMed:21199876). {ECO:0000250, ECO:0000269|PubMed:21199876}. CC -!- SIMILARITY: Belongs to the SPSB family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF403029; AAL57348.1; -; mRNA. DR EMBL; AK056367; BAB71165.1; -; mRNA. DR EMBL; BC008324; AAH08324.1; -; mRNA. DR CCDS; CCDS3115.1; -. DR RefSeq; NP_543138.1; NM_080862.2. DR PDB; 2V24; X-ray; 2.20 A; A=33-233. DR PDB; 6DN7; X-ray; 1.40 A; A/C=28-233. DR PDB; 6DN8; X-ray; 1.75 A; A/C/E=28-233. DR PDBsum; 2V24; -. DR PDBsum; 6DN7; -. DR PDBsum; 6DN8; -. DR SMR; Q96A44; -. DR BioGRID; 124941; 11. DR ELM; Q96A44; -. DR IntAct; Q96A44; 7. DR STRING; 9606.ENSP00000311609; -. DR iPTMnet; Q96A44; -. DR PhosphoSitePlus; Q96A44; -. DR BioMuta; SPSB4; -. DR DMDM; 74731085; -. DR MassIVE; Q96A44; -. DR PaxDb; Q96A44; -. DR PeptideAtlas; Q96A44; -. DR PRIDE; Q96A44; -. DR ProteomicsDB; 75907; -. DR Antibodypedia; 77081; 11 antibodies. DR DNASU; 92369; -. DR Ensembl; ENST00000310546; ENSP00000311609; ENSG00000175093. DR GeneID; 92369; -. DR KEGG; hsa:92369; -. DR UCSC; uc003ett.4; human. DR CTD; 92369; -. DR DisGeNET; 92369; -. DR GeneCards; SPSB4; -. DR HGNC; HGNC:30630; SPSB4. DR HPA; ENSG00000175093; Tissue enriched (pancreas). DR MIM; 611660; gene. DR neXtProt; NX_Q96A44; -. DR OpenTargets; ENSG00000175093; -. DR PharmGKB; PA142670874; -. DR VEuPathDB; HostDB:ENSG00000175093.4; -. DR eggNOG; KOG3953; Eukaryota. DR GeneTree; ENSGT01030000234629; -. DR HOGENOM; CLU_046756_0_1_1; -. DR InParanoid; Q96A44; -. DR OMA; DLCRRCI; -. DR OrthoDB; 938259at2759; -. DR PhylomeDB; Q96A44; -. DR TreeFam; TF312822; -. DR PathwayCommons; Q96A44; -. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR UniPathway; UPA00143; -. DR BioGRID-ORCS; 92369; 7 hits in 982 CRISPR screens. DR ChiTaRS; SPSB4; human. DR EvolutionaryTrace; Q96A44; -. DR GenomeRNAi; 92369; -. DR Pharos; Q96A44; Tdark. DR PRO; PR:Q96A44; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q96A44; protein. DR Bgee; ENSG00000175093; Expressed in testis and 122 other tissues. DR ExpressionAtlas; Q96A44; baseline and differential. DR Genevisible; Q96A44; HS. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0019005; C:SCF ubiquitin ligase complex; IBA:GO_Central. DR GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; IPI:UniProtKB. DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro. DR GO; GO:1902916; P:positive regulation of protein polyubiquitination; IDA:UniProtKB. DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome. DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IBA:GO_Central. DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB. DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB. DR GO; GO:0048511; P:rhythmic process; IEA:UniProtKB-KW. DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; IDA:UniProtKB. DR Gene3D; 2.60.120.920; -; 1. DR InterPro; IPR001870; B30.2/SPRY. DR InterPro; IPR043136; B30.2/SPRY_sf. DR InterPro; IPR013320; ConA-like_dom_sf. DR InterPro; IPR001496; SOCS_box. DR InterPro; IPR036036; SOCS_box-like_dom_sf. DR InterPro; IPR003877; SPRY_dom. DR Pfam; PF07525; SOCS_box; 1. DR Pfam; PF00622; SPRY; 1. DR SMART; SM00969; SOCS_box; 1. DR SMART; SM00449; SPRY; 1. DR SUPFAM; SSF158235; SSF158235; 1. DR SUPFAM; SSF49899; SSF49899; 1. DR PROSITE; PS50188; B302_SPRY; 1. DR PROSITE; PS50225; SOCS; 1. PE 1: Evidence at protein level; KW 3D-structure; Biological rhythms; Cytoplasm; Reference proteome; KW Ubl conjugation pathway. FT CHAIN 1..273 FT /note="SPRY domain-containing SOCS box protein 4" FT /id="PRO_0000238477" FT DOMAIN 34..233 FT /note="B30.2/SPRY" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00548" FT DOMAIN 234..273 FT /note="SOCS box" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00194" FT REGION 1..34 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 16..32 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT HELIX 35..42 FT /evidence="ECO:0007829|PDB:6DN7" FT HELIX 48..53 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 55..61 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 65..67 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 74..77 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 83..90 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 93..103 FT /evidence="ECO:0007829|PDB:6DN7" FT HELIX 106..108 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 114..118 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 124..129 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 139..143 FT /evidence="ECO:0007829|PDB:6DN7" FT TURN 144..147 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 148..152 FT /evidence="ECO:0007829|PDB:6DN7" FT TURN 153..155 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 159..162 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 175..182 FT /evidence="ECO:0007829|PDB:6DN7" FT TURN 183..186 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 187..192 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 195..201 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 209..215 FT /evidence="ECO:0007829|PDB:6DN7" FT STRAND 217..219 FT /evidence="ECO:0007829|PDB:2V24" FT STRAND 221..230 FT /evidence="ECO:0007829|PDB:6DN7" SQ SEQUENCE 273 AA; 30179 MW; 234A651A08217489 CRC64; MGQKLSGSLK SVEVREPALR PAKRELRGAE PGRPARLDQL LDMPAAGLAV QLRHAWNPED RSLNVFVKDD DRLTFHRHPV AQSTDGIRGK VGHARGLHAW QINWPARQRG THAVVGVATA RAPLHSVGYT ALVGSDAESW GWDLGRSRLY HDGKNQPGVA YPAFLGPDEA FALPDSLLVV LDMDEGTLSF IVDGQYLGVA FRGLKGKKLY PVVSAVWGHC EVTMRYINGL DPEPLPLMDL CRRSIRSALG RQRLQDISSL PLPQSLKNYL QYQ //