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   27-MAR-2024, entry version 166.
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; 116.
DR   IntAct; Q9H173; 28.
DR   MINT; Q9H173; -.
DR   STRING; 9606.ENSP00000265195; -.
DR   GlyConnect; 1581; 2 N-Linked glycans (1 site).
DR   GlyCosmos; Q9H173; 4 sites, 5 glycans.
DR   GlyGen; Q9H173; 13 sites, 3 N-linked glycans (1 site), 3 O-linked glycans (11 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; 9606-ENSP00000378294; -.
DR   PeptideAtlas; Q9H173; -.
DR   ProteomicsDB; 80376; -.
DR   Pumba; Q9H173; -.
DR   Antibodypedia; 2386; 362 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   AGR; HGNC:24624; -.
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; 67078at2759; -.
DR   PhylomeDB; Q9H173; -.
DR   TreeFam; TF324307; -.
DR   PathwayCommons; Q9H173; -.
DR   SignaLink; Q9H173; -.
DR   SIGNOR; Q9H173; -.
DR   BioGRID-ORCS; 64374; 13 hits in 1166 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 166 other cell types or tissues.
DR   ExpressionAtlas; Q9H173; baseline and differential.
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; Leucine-rich Repeat Variant; 1.
DR   InterPro; IPR011989; ARM-like.
DR   InterPro; IPR016024; ARM-type_fold.
DR   InterPro; IPR013918; Nucleotide_exch_fac_Fes1.
DR   PANTHER; PTHR19316:SF35; NUCLEOTIDE EXCHANGE FACTOR SIL1; 1.
DR   PANTHER; PTHR19316; PROTEIN FOLDING REGULATOR; 1.
DR   Pfam; PF08609; Fes1; 1.
DR   SUPFAM; SSF48371; ARM repeat; 1.
DR   Genevisible; Q9H173; HS.
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
//