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 18-SEP-2019, entry version 141. 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; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 RT project: 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 RP WITH CUL5; RNF7; ELOB AND ELOC. RX PubMed=15601820; DOI=10.1101/gad.1252404; RA Kamura T., Maenaka K., Kotoshiba S., Matsumoto M., Kohda D., RA Conaway R.C., Conaway J.W., Nakayama K.I.; RT "VHL-box and SOCS-box domains determine binding specificity for Cul2- RT Rbx1 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 RT MET and enhances the hepatocyte growth factor-induced Erk-Elk-1-serum RT response element pathway."; RL J. Biol. Chem. 280:16393-16401(2005). RN [6] RP FUNCTION, INTERACTION WITH NOS2, SUBCELLULAR LOCATION, AND DOMAIN SOCS RP 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 RT SOCS 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 RT mammalian 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., RA Fukui Y., Nakatsukasa K., Kamura T.; RT "Ubiquitin ligase SPSB4 diminishes cell repulsive responses mediated RT by EphB2."; RL Mol. Biol. Cell 28:3532-3541(2017). RN [9] {ECO:0000244|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., RA Kuang Z., Savitsky P., Lewis R.S., Nicholson S.E., Norton R.S., RA Bullock A.N.; RT "Structural basis for Par-4 recognition by the SPRY domain- and SOCS RT box-containing proteins SPSB1, SPSB2, and SPSB4."; RL J. Mol. Biol. 401:389-402(2010). CC -!- FUNCTION: Substrate recognition component of a SCF-like ECS CC (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase CC complex which mediates the ubiquitination and subsequent CC proteasomal degradation of target proteins (PubMed:21199876, CC PubMed:15601820). Negatively regulates nitric oxide (NO) CC production and limits cellular toxicity in activated macrophages CC by mediating the ubiquitination and proteasomal degradation of CC NOS2 (PubMed:21199876). Acts as a bridge which links NOS2 with the CC ECS E3 ubiquitin ligase complex components ELOC and CUL5 CC (PubMed:21199876). Diminishes EphB2-dependent cell repulsive CC responses by mediating the ubiquitination and degradation of CC EphB2/CTF2 (PubMed:28931592). Regulates cellular clock function by CC mediating the ubiquitin/proteasome-dependent degradation of the CC circadian 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 CC and SPSB4 (PubMed:15601820). Interacts with CUL5; RNF7; ELOB and CC ELOC (PubMed:15601820). Interacts with MET (PubMed:15713673). CC Interacts (via B30.2/SPRY domain) with PAWR; this interaction CC occurs in association with the Elongin BC complex CC (PubMed:20561531). Interacts with NOS2 (PubMed:21199876). CC 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 Q15369:ELOC; NbExp=2; IntAct=EBI-2323233, EBI-301231; 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 CC Elongin BC complex, an adapter module in different E3 ubiquitin CC ligase complexes (By similarity). Essential for its ability to CC link NOS2 and the ECS E3 ubiquitin ligase complex components ELOC CC and CUL5 (PubMed:21199876). {ECO:0000250, CC 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; 10. DR ELM; Q96A44; -. DR IntAct; Q96A44; 6. DR STRING; 9606.ENSP00000311609; -. DR iPTMnet; Q96A44; -. DR PhosphoSitePlus; Q96A44; -. DR BioMuta; SPSB4; -. DR DMDM; 74731085; -. DR jPOST; Q96A44; -. DR MassIVE; Q96A44; -. DR PaxDb; Q96A44; -. DR PeptideAtlas; Q96A44; -. DR PRIDE; Q96A44; -. DR ProteomicsDB; 75907; -. 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; HPA062793; -. DR MIM; 611660; gene. DR neXtProt; NX_Q96A44; -. DR OpenTargets; ENSG00000175093; -. DR PharmGKB; PA142670874; -. DR eggNOG; KOG3953; Eukaryota. DR eggNOG; ENOG410XQC1; LUCA. DR GeneTree; ENSGT00950000182795; -. DR HOGENOM; HOG000230524; -. DR InParanoid; Q96A44; -. DR KO; K10343; -. DR OMA; CKNQPGV; -. DR OrthoDB; 938259at2759; -. DR PhylomeDB; Q96A44; -. DR TreeFam; TF312822; -. DR Reactome; R-HSA-8951664; Neddylation. DR Reactome; R-HSA-983168; Antigen processing: Ubiquitination & Proteasome degradation. DR UniPathway; UPA00143; -. DR ChiTaRS; SPSB4; human. DR EvolutionaryTrace; Q96A44; -. DR GenomeRNAi; 92369; -. DR Pharos; Q96A44; -. DR PRO; PR:Q96A44; -. DR Proteomes; UP000005640; Chromosome 3. DR Bgee; ENSG00000175093; Expressed in 95 organ(s), highest expression level in testis. 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:protein binding, bridging involved in substrate recognition for ubiquitination; 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 InterPro; IPR001870; B30.2/SPRY. 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; Complete proteome; Cytoplasm; KW Reference proteome; Ubl conjugation pathway. FT CHAIN 1 273 SPRY domain-containing SOCS box protein FT 4. FT /FTId=PRO_0000238477. FT DOMAIN 34 233 B30.2/SPRY. {ECO:0000255|PROSITE- FT ProRule:PRU00548}. FT DOMAIN 234 273 SOCS box. {ECO:0000255|PROSITE- FT ProRule:PRU00194}. FT HELIX 35 42 {ECO:0000244|PDB:6DN7}. FT HELIX 48 53 {ECO:0000244|PDB:6DN7}. FT STRAND 55 61 {ECO:0000244|PDB:6DN7}. FT STRAND 65 67 {ECO:0000244|PDB:6DN7}. FT STRAND 74 77 {ECO:0000244|PDB:6DN7}. FT STRAND 83 90 {ECO:0000244|PDB:6DN7}. FT STRAND 93 103 {ECO:0000244|PDB:6DN7}. FT HELIX 106 108 {ECO:0000244|PDB:6DN7}. FT STRAND 114 118 {ECO:0000244|PDB:6DN7}. FT STRAND 124 129 {ECO:0000244|PDB:6DN7}. FT STRAND 139 143 {ECO:0000244|PDB:6DN7}. FT TURN 144 147 {ECO:0000244|PDB:6DN7}. FT STRAND 148 152 {ECO:0000244|PDB:6DN7}. FT TURN 153 155 {ECO:0000244|PDB:6DN7}. FT STRAND 159 162 {ECO:0000244|PDB:6DN7}. FT STRAND 175 182 {ECO:0000244|PDB:6DN7}. FT TURN 183 186 {ECO:0000244|PDB:6DN7}. FT STRAND 187 192 {ECO:0000244|PDB:6DN7}. FT STRAND 195 201 {ECO:0000244|PDB:6DN7}. FT STRAND 209 215 {ECO:0000244|PDB:6DN7}. FT STRAND 217 219 {ECO:0000244|PDB:2V24}. FT STRAND 221 230 {ECO:0000244|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 //