SIL1_HUMAN
ID SIL1_HUMAN Reviewed; 461 AA.
AC Q9H173; D3DQC2; Q8N2L3;
DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2001, sequence version 1.
DT 03-AUG-2022, entry version 157.
DE RecName: Full=Nucleotide exchange factor SIL1;
DE AltName: Full=BiP-associated protein;
DE Short=BAP;
DE Flags: Precursor;
GN Name=SIL1; ORFNames=UNQ545/PRO836;
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].
RX PubMed=11101517; DOI=10.1093/emboj/19.23.6440;
RA Tyson J.R., Stirling C.J.;
RT "LHS1 and SIL1 provide a lumenal function that is essential for protein
RT translocation into the endoplasmic reticulum.";
RL EMBO J. 19:6440-6452(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH HSPA5, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, AND GLYCOSYLATION.
RX PubMed=12356756; DOI=10.1074/jbc.m208377200;
RA Chung K.T., Shen Y., Hendershot L.M.;
RT "BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor
RT that regulates the ATPase activity of BiP.";
RL J. Biol. Chem. 277:47557-47563(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Embryo, and Placenta;
RX PubMed=16303743; DOI=10.1093/dnares/12.2.117;
RA Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J.,
RA Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S.,
RA Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y.,
RA Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S.,
RA Isogai T.;
RT "Signal sequence and keyword trap in silico for selection of full-length
RT human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA
RT libraries.";
RL DNA Res. 12:117-126(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
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 [7]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND
RP INVOLVEMENT IN MSS.
RX PubMed=16282978; DOI=10.1038/ng1677;
RA Anttonen A.-K., Mahjneh I., Haemaelaeinen R.H., Lagier-Tourenne C.,
RA Kopra O., Waris L., Anttonen M., Joensuu T., Kalimo H., Paetau A.,
RA Tranebjaerg L., Chaigne D., Koenig M., Eeg-Olofsson O., Udd B., Somer M.,
RA Somer H., Lehesjoki A.-E.;
RT "The gene disrupted in Marinesco-Sjoegren syndrome encodes SIL1, an HSPA5
RT cochaperone.";
RL Nat. Genet. 37:1309-1311(2005).
RN [8]
RP INVOLVEMENT IN MSS.
RX PubMed=16282977; DOI=10.1038/ng1678;
RA Senderek J., Krieger M., Stendel C., Bergmann C., Moser M.,
RA Breitbach-Faller N., Rudnik-Schoeneborn S., Blaschek A., Wolf N.I.,
RA Harting I., North K., Smith J., Muntoni F., Brockington M., Quijano-Roy S.,
RA Renault F., Herrmann R., Hendershot L.M., Schroeder J.M., Lochmueller H.,
RA Topaloglu H., Voit T., Weis J., Ebinger F., Zerres K.;
RT "Mutations in SIL1 cause Marinesco-Sjoegren syndrome, a cerebellar ataxia
RT with cataract and myopathy.";
RL Nat. Genet. 37:1312-1314(2005).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-193.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP UBIQUITINATION.
RX PubMed=33398170; DOI=10.1038/s41589-020-00703-4;
RA Yan X., Wang X., Li Y., Zhou M., Li Y., Song L., Mi W., Min J., Dong C.;
RT "Molecular basis for ubiquitin ligase CRL2FEM1C-mediated recognition of C-
RT degron.";
RL Nat. Chem. Biol. 17:263-271(2021).
RN [12] {ECO:0007744|PDB:6LBN, ECO:0007744|PDB:6LEY}
RP X-RAY CRYSTALLOGRAPHY (2.39 ANGSTROMS) OF 452-461 IN COMPLEX WITH FEM1C,
RP AND UBIQUITINATION.
RX PubMed=33398168; DOI=10.1038/s41589-020-00704-3;
RA Chen X., Liao S., Makaros Y., Guo Q., Zhu Z., Krizelman R., Dahan K.,
RA Tu X., Yao X., Koren I., Xu C.;
RT "Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3
RT ligase.";
RL Nat. Chem. Biol. 17:254-262(2021).
CC -!- FUNCTION: Required for protein translocation and folding in the
CC endoplasmic reticulum (ER). Functions as a nucleotide exchange factor
CC for the ER lumenal chaperone HSPA5. {ECO:0000269|PubMed:12356756}.
CC -!- SUBUNIT: Interacts with HSPA5. {ECO:0000269|PubMed:12356756}.
CC -!- INTERACTION:
CC Q9H173; P11021: HSPA5; NbExp=9; IntAct=EBI-2840325, EBI-354921;
CC Q9H173; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-2840325, EBI-744081;
CC Q9H173; Q9H173: SIL1; NbExp=6; IntAct=EBI-2840325, EBI-2840325;
CC Q9H173; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-2840325, EBI-741480;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum lumen
CC {ECO:0000269|PubMed:12356756, ECO:0000269|PubMed:16282978}.
CC -!- TISSUE SPECIFICITY: Highly expressed in tissues which produce large
CC amounts of secreted proteins such as kidney, liver and placenta. Also
CC expressed in colon, heart, lung, ovary, pancreas, peripheral leukocyte,
CC prostate, spleen and thymus. Expressed at low levels throughout the
CC brain. {ECO:0000269|PubMed:12356756, ECO:0000269|PubMed:16282978}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal kidney, fetal lung, fetal liver
CC and at low levels in fetal brain. {ECO:0000269|PubMed:16282978}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:12356756,
CC ECO:0000269|PubMed:19159218}.
CC -!- PTM: Ubiquitinated by the CRL2(FEM1A) and CRL2(FEM1C) complexes, which
CC recognize the -Lys-Xaa-Xaa-Arg C-degron at the C-terminus, leading to
CC its degradation. {ECO:0000269|PubMed:33398168,
CC ECO:0000269|PubMed:33398170}.
CC -!- DISEASE: Marinesco-Sjoegren syndrome (MSS) [MIM:248800]: Autosomal
CC recessive multisystem disorder which is characterized by cerebellar
CC ataxia due to cerebellar atrophy, with Purkinje and granule cell loss
CC and myopathy featuring marked muscle replacement with fat and
CC connective tissue. Other cardinal features include bilateral cataracts,
CC hypergonadotrophic hypogonadism and mild to severe intellectual
CC disability. Skeletal abnormalities, short stature, dysarthria,
CC strabismus and nystagmus are also frequent findings. Mutational
CC inactivation of this protein may result in ER stress-induced cell death
CC signaling or malfunctioning chaperone machineries that mishandle client
CC proteins which are critical for the organs targeted in MSS.
CC {ECO:0000269|PubMed:16282977, ECO:0000269|PubMed:16282978}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the SIL1 family. {ECO:0000305}.
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DR EMBL; AJ299442; CAC17773.1; -; mRNA.
DR EMBL; AF547994; AAN84477.1; -; mRNA.
DR EMBL; AY358950; AAQ89309.1; -; mRNA.
DR EMBL; AK074624; BAC11096.1; -; mRNA.
DR EMBL; AK075177; BAC11452.1; -; mRNA.
DR EMBL; CH471062; EAW62120.1; -; Genomic_DNA.
DR EMBL; CH471062; EAW62121.1; -; Genomic_DNA.
DR EMBL; BC011568; AAH11568.1; -; mRNA.
DR CCDS; CCDS4209.1; -.
DR RefSeq; NP_001032722.1; NM_001037633.1.
DR RefSeq; NP_071909.1; NM_022464.4.
DR PDB; 6LBN; X-ray; 2.90 A; A/B=452-461.
DR PDB; 6LEY; X-ray; 2.39 A; A/B=452-461.
DR PDBsum; 6LBN; -.
DR PDBsum; 6LEY; -.
DR AlphaFoldDB; Q9H173; -.
DR SMR; Q9H173; -.
DR BioGRID; 122145; 107.
DR IntAct; Q9H173; 28.
DR MINT; Q9H173; -.
DR STRING; 9606.ENSP00000378294; -.
DR GlyConnect; 1581; 2 N-Linked glycans (1 site).
DR GlyGen; Q9H173; 4 sites, 2 N-linked glycans (1 site), 2 O-linked glycans (2 sites).
DR iPTMnet; Q9H173; -.
DR PhosphoSitePlus; Q9H173; -.
DR BioMuta; SIL1; -.
DR DMDM; 74733533; -.
DR EPD; Q9H173; -.
DR jPOST; Q9H173; -.
DR MassIVE; Q9H173; -.
DR MaxQB; Q9H173; -.
DR PaxDb; Q9H173; -.
DR PeptideAtlas; Q9H173; -.
DR PRIDE; Q9H173; -.
DR ProteomicsDB; 80376; -.
DR Antibodypedia; 2386; 325 antibodies from 33 providers.
DR DNASU; 64374; -.
DR Ensembl; ENST00000265195.9; ENSP00000265195.5; ENSG00000120725.13.
DR Ensembl; ENST00000394817.7; ENSP00000378294.2; ENSG00000120725.13.
DR GeneID; 64374; -.
DR KEGG; hsa:64374; -.
DR MANE-Select; ENST00000394817.7; ENSP00000378294.2; NM_022464.5; NP_071909.1.
DR UCSC; uc003ldo.4; human.
DR CTD; 64374; -.
DR DisGeNET; 64374; -.
DR GeneCards; SIL1; -.
DR GeneReviews; SIL1; -.
DR HGNC; HGNC:24624; SIL1.
DR HPA; ENSG00000120725; Low tissue specificity.
DR MalaCards; SIL1; -.
DR MIM; 248800; phenotype.
DR MIM; 608005; gene.
DR neXtProt; NX_Q9H173; -.
DR OpenTargets; ENSG00000120725; -.
DR Orphanet; 559; Marinesco-Sjoegren syndrome.
DR PharmGKB; PA142670916; -.
DR VEuPathDB; HostDB:ENSG00000120725; -.
DR eggNOG; KOG2160; Eukaryota.
DR GeneTree; ENSGT00940000153909; -.
DR InParanoid; Q9H173; -.
DR OMA; FQPTHEW; -.
DR OrthoDB; 1501690at2759; -.
DR PhylomeDB; Q9H173; -.
DR TreeFam; TF324307; -.
DR PathwayCommons; Q9H173; -.
DR SignaLink; Q9H173; -.
DR SIGNOR; Q9H173; -.
DR BioGRID-ORCS; 64374; 12 hits in 1085 CRISPR screens.
DR ChiTaRS; SIL1; human.
DR GeneWiki; SIL1; -.
DR GenomeRNAi; 64374; -.
DR Pharos; Q9H173; Tbio.
DR PRO; PR:Q9H173; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q9H173; protein.
DR Bgee; ENSG00000120725; Expressed in islet of Langerhans and 164 other tissues.
DR ExpressionAtlas; Q9H173; baseline and differential.
DR Genevisible; Q9H173; HS.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:FlyBase.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR GO; GO:0000774; F:adenyl-nucleotide exchange factor activity; IDA:FlyBase.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0051082; F:unfolded protein binding; NAS:UniProtKB.
DR GO; GO:0006613; P:cotranslational protein targeting to membrane; ISS:FlyBase.
DR GO; GO:0006886; P:intracellular protein transport; NAS:UniProtKB.
DR GO; GO:0006457; P:protein folding; NAS:UniProtKB.
DR Gene3D; 1.25.10.10; -; 1.
DR InterPro; IPR011989; ARM-like.
DR InterPro; IPR016024; ARM-type_fold.
DR SUPFAM; SSF48371; SSF48371; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disease variant; Endoplasmic reticulum; Glycoprotein;
KW Protein transport; Reference proteome; Signal; Translocation; Transport;
KW Ubl conjugation.
FT SIGNAL 1..31
FT /evidence="ECO:0000255"
FT CHAIN 32..461
FT /note="Nucleotide exchange factor SIL1"
FT /id="PRO_0000223354"
FT REGION 1..256
FT /note="Interaction with HSPA5 and localization to the
FT endoplasmic reticulum"
FT /evidence="ECO:0000250|UniProtKB:Q9EPK6"
FT CARBOHYD 193
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT CARBOHYD 236
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 80
FT /note="Q -> R (in dbSNP:rs35581768)"
FT /id="VAR_034495"
FT CONFLICT 57
FT /note="K -> E (in Ref. 4; BAC11096)"
FT /evidence="ECO:0000305"
FT TURN 456..459
FT /evidence="ECO:0007829|PDB:6LBN"
SQ SEQUENCE 461 AA; 52085 MW; C4DD7E880A610880 CRC64;
MAPQSLPSSR MAPLGMLLGL LMAACFTFCL SHQNLKEFAL TNPEKSSTKE TERKETKAEE
ELDAEVLEVF HPTHEWQALQ PGQAVPAGSH VRLNLQTGER EAKLQYEDKF RNNLKGKRLD
INTNTYTSQD LKSALAKFKE GAEMESSKED KARQAEVKRL FRPIEELKKD FDELNVVIET
DMQIMVRLIN KFNSSSSSLE EKIAALFDLE YYVHQMDNAQ DLLSFGGLQV VINGLNSTEP
LVKEYAAFVL GAAFSSNPKV QVEAIEGGAL QKLLVILATE QPLTAKKKVL FALCSLLRHF
PYAQRQFLKL GGLQVLRTLV QEKGTEVLAV RVVTLLYDLV TEKMFAEEEA ELTQEMSPEK
LQQYRQVHLL PGLWEQGWCE ITAHLLALPE HDAREKVLQT LGVLLTTCRD RYRQDPQLGR
TLASLQAEYQ VLASLELQDG EDEGYFQELL GSVNSLLKEL R
