SPSB4_HUMAN
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 03-AUG-2022, entry version 155.
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}.
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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 AlphaFoldDB; Q96A44; -.
DR SMR; Q96A44; -.
DR BioGRID; 124941; 127.
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; 12 antibodies from 8 providers.
DR DNASU; 92369; -.
DR Ensembl; ENST00000310546.3; ENSP00000311609.2; ENSG00000175093.5.
DR GeneID; 92369; -.
DR KEGG; hsa:92369; -.
DR MANE-Select; ENST00000310546.3; ENSP00000311609.2; NM_080862.3; NP_543138.1.
DR UCSC; uc003ett.4; human.
DR CTD; 92369; -.
DR DisGeNET; 92369; -.
DR GeneCards; SPSB4; -.
DR HGNC; HGNC:30630; SPSB4.
DR HPA; ENSG00000175093; Tissue enhanced (brain, pancreas, pituitary gland, testis).
DR MIM; 611660; gene.
DR neXtProt; NX_Q96A44; -.
DR OpenTargets; ENSG00000175093; -.
DR PharmGKB; PA142670874; -.
DR VEuPathDB; HostDB:ENSG00000175093; -.
DR eggNOG; KOG3953; Eukaryota.
DR GeneTree; ENSGT01030000234629; -.
DR HOGENOM; CLU_046756_0_1_1; -.
DR InParanoid; Q96A44; -.
DR OMA; SWNADDR; -.
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 SignaLink; Q96A44; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 92369; 11 hits in 1067 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 sperm and 129 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: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
