This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized.[8]
In the mid-1990s, several laboratories independently discovered Sil1 in three different organisms. A conditional lethality screen was used in the yeast Yarrowia lipolytica to detect cellular components that interacted with the 7S RNA or the signal recognition particle (SRP) during co-translational translocation, which led to the identification of the Sls1p gene. Sls1p is an ER-luminal, 54 kDa protein that contains an N-terminal signal sequence and a C-terminal ER-retention motif.[9] Sls1p fractionated with the membranous fraction and was shown to interact with the Sec61p translocation apparatus. Sls1p was induced by ER stresses, such as heat shock or inhibition of glycosylation, and its deletion resulted in decreased maturation of secretory proteins. This protein also bound to the ADP-bound form of Kar2p, the yeast homolog of BiP, and stimulated its interaction with Sec63, a DnaJ family member and a translocon component. Disruption of the interaction between Sls1p and Kar2p significantly affected the secretion of a reporter protein, leading the investigators to conclude that Sls1p assisted BiP in the translocation of nascent proteins into the ER lumen. Another group working with Saccharomyces cerevisiae conducted a screen for genes that would suppress the severe growth defect observed in the ΔIre1ΔLhs1 yeast double mutants when overexpressed and named this gene the suppressor of Ire1 and Lhs1 deletion 1 (Sil1). Sil1p was shown to be a homolog of Sls1p, and a combined deletion of Sil1p and Lhs1 (yeast GRP170) proved to be lethal after causing a total block in protein translocation into the ER. Mammalian (human) SIL1 was discovered in a yeast two-hybrid screen aimed at identifying proteins that interacted with a mutant ATPase domain of BiP and was initially named BiP-associated protein (BAP). Sequence analysis revealed that BAP is a mammalian homolog of Sls1p and Sil1p and is similar to the cytosolic HSP70-binding protein, HSPBP1. Biochemical data further demonstrated that BAP also had NEF activity for BiP.
Structure and mechanism of nucleotide exchangeedit
Structural data for yeast Sil1p revealed an elongated, “kidney bean”-like molecular shape that consists of 16 α-helices (A1–A16) and lacks β-sheets. The central helices A3-A14 form the armadillo (ARM)-like repeats (ARM1-ARM4), which are named after those found in β-catenin. Each ARM repeat is composed of three α-helices that pack into a superhelix. A crystal structure of yeast Sil1p complexed with the ADP-bound NBD of Kar2p/BiP revealed that the ARM domain of Sil1p wraps around lobe IIb of BiP’s NBD and makes additional contacts with lobe Ib. This interaction causes lobes Ib and IIb to rotate away from each other, leading to ADP release. Point mutations in the Sil1p-interacting site of Kar2p’s NBD specifically disrupted Sil1p binding but retained Kar2p’s ability to interact with Lhs1/GRP170, the other ER NEF, providing the first indication that their mechanisms of NEF activity were different. Homology mapping and comparisons with the structure of cytosolic HSPBP1 indicated that the region of SIL1 encoded by exons 6 and 9 constitutes major BiP-binding sites, and exon 10 encodes a minor interaction site.
Tissue expressionedit
Although SIL1 is ubiquitously expressed, levels vary widely by tissue. The Human Protein Atlas (www.proteinatlas.org) shows that the expression pattern of SIL1 mirrors that of BiP even more closely than that of GRP170, which is a known UPR target, as is BiP. Perhaps the different expression pattern for GRP170 is due to its dual function as a chaperone and a NEF for BiP. SIL1 expression at a single-cell level has also been determined in a number of tissues, which does not strictly correlate with the secretory capacity of the cell, and tissues displaying the highest relative levels of SIL1 are not necessarily those most affected by loss of its function. This might imply an additional function, which has been demonstrated for Sil1p, or an as yet undiscovered role of SIL1 in certain tissues. Understanding this reason for variation in tissue expression will require further studies.
^ abcdefGRCh38: Ensembl release 89: ENSG00000120725 – Ensembl, May 2017
^ abcdefGRCm38: Ensembl release 89: ENSMUSG00000024357 – Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Tyson JR, Stirling CJ (December 2000). "LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum". The EMBO Journal. 19 (23): 6440–52. doi:10.1093/emboj/19.23.6440. PMC305876. PMID 11101517.
^ abChung KT, Shen Y, Hendershot LM (December 2002). "BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP". The Journal of Biological Chemistry. 277 (49): 47557–63. doi:10.1074/jbc.M208377200. PMID 12356756.
^Senderek J, Krieger M, Stendel C, Bergmann C, Moser M, Breitbach-Faller N, et al. (December 2005). "Mutations in SIL1 cause Marinesco-Sjögren syndrome, a cerebellar ataxia with cataract and myopathy". Nature Genetics. 37 (12): 1312–4. doi:10.1038/ng1678. PMID 16282977. S2CID 28860307.
^Ichhaporia VP, Hendershot LM (February 2021). "Role of the HSP70 Co-Chaperone SIL1 in Health and Disease". International Journal of Molecular Sciences. 22 (4): 1564. doi:10.3390/ijms22041564. PMC7913895. PMID 33557244.
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
Further readingedit
Ichhaporia VP, Kim J, Kavdia K, Vogel P, Horner L, Frase S, Hendershot LM (May 2018). "SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology". Disease Models & Mechanisms. 11 (5): dmm033043. doi:10.1242/dmm.033043. PMC5992605. PMID 29666155.
Ichhaporia VP, Sanford T, Howes J, Marion TN, Hendershot LM (February 2015). "Sil1, a nucleotide exchange factor for BiP, is not required for antibody assembly or secretion". Molecular Biology of the Cell. 26 (3): 420–9. doi:10.1091/mbc.E14-09-1392. PMC4310734. PMID 25473114.
Keats B, Ott J, Conneally M (1989). "Report of the committee on linkage and gene order". Cytogenetics and Cell Genetics. 51 (1–4): 459–502. doi:10.1159/000132805. PMID 2791656.
Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, et al. (October 2003). "The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment". Genome Research. 13 (10): 2265–70. doi:10.1101/gr.1293003. PMC403697. PMID 12975309.
Lagier-Tourenne C, Tranebaerg L, Chaigne D, Gribaa M, Dollfus H, Silvestri G, et al. (October 2003). "Homozygosity mapping of Marinesco-Sjögren syndrome to 5q31". European Journal of Human Genetics. 11 (10): 770–8. doi:10.1038/sj.ejhg.5201068. PMID 14512967.
Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, et al. (July 2004). "Functional proteomics mapping of a human signaling pathway". Genome Research. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC442148. PMID 15231748.
Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
Anttonen AK, Mahjneh I, Hämäläinen RH, Lagier-Tourenne C, Kopra O, Waris L, et al. (December 2005). "The gene disrupted in Marinesco-Sjögren syndrome encodes SIL1, an HSPA5 cochaperone". Nature Genetics. 37 (12): 1309–11. doi:10.1038/ng1677. PMID 16282978. S2CID 33094308.
Otsuki T, Ota T, Nishikawa T, Hayashi K, Suzuki Y, Yamamoto J, et al. (2007). "Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries". DNA Research. 12 (2): 117–26. doi:10.1093/dnares/12.2.117. PMID 16303743.
Karim MA, Parsian AJ, Cleves MA, Bracey J, Elsayed MS, Elsobky E, Parsian A (November 2006). "A novel mutation in BAP/SIL1 gene causes Marinesco-Sjögren syndrome in an extended pedigree". Clinical Genetics. 70 (5): 420–3. doi:10.1111/j.1399-0004.2006.00695.x. PMID 17026626. S2CID 28527790.
External linksedit
GeneReviews/NCBI/NIH/UW entry on Marinesco-Sjögren Syndrome
This article on a gene on human chromosome 5 is a stub. You can help Wikipedia by expanding it.
sil1, nucleotide, exchange, factor, protein, that, humans, encoded, gene, identifiersaliases, ulg5, nucleotide, exchange, factorexternal, idsomim, 608005, 1932040, homologene, 32544, genecards, gene, location, human, chromosome, human, band5q31, 2start138, end. Nucleotide exchange factor SIL1 is a protein that in humans is encoded by the SIL1 gene 5 6 7 8 SIL1IdentifiersAliasesSIL1 BAP MSS ULG5 SIL1 nucleotide exchange factorExternal IDsOMIM 608005 MGI 1932040 HomoloGene 32544 GeneCards SIL1Gene location Human Chr Chromosome 5 human 1 Band5q31 2Start138 946 724 bp 1 End139 293 557 bp 1 Gene location Mouse Chr Chromosome 18 mouse 2 Band18 18 B1 B2Start35 399 449 bp 2 End35 632 833 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inislet of Langerhansbody of pancreasstromal cell of endometriumright adrenal glandleft adrenal glandright lobe of liversural nerveAchilles tendonanterior pituitaryright lobe of thyroid glandTop expressed inspermatocytespermatidlacrimal glandparotid glandseminal vesiculaleft lobe of liverseminiferous tubuleproximal tubuleutriclesupraoptic nucleusMore reference expression dataBioGPSMore reference expression dataGene ontologyMolecular functionunfolded protein binding protein binding adenyl nucleotide exchange factor activityCellular componentendoplasmic reticulum lumen endoplasmic reticulum extracellular space cytoplasmBiological processprotein folding protein transport intracellular protein transport transport regulation of catalytic activitySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez6437481500EnsemblENSG00000120725ENSMUSG00000024357UniProtQ9H173Q9EPK6RefSeq mRNA NM 001037633NM 022464NM 030749NM 001360814RefSeq protein NP 001032722NP 071909NP 109674NP 001347743Location UCSC Chr 5 138 95 139 29 MbChr 18 35 4 35 63 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse This gene encodes a resident endoplasmic reticulum ER N linked glycoprotein with an N terminal ER targeting sequence 2 putative N glycosylation sites and a C terminal ER retention signal This protein functions as a nucleotide exchange factor for another unfolded protein response protein Mutations in this gene have been associated with Marinesco Sjogren syndrome Alternate transcriptional splice variants have been characterized 8 Contents 1 Discovery and expression 2 Structure and mechanism of nucleotide exchange 3 Tissue expression 4 Interactions 5 References 6 Further reading 7 External linksDiscovery and expression editIn the mid 1990s several laboratories independently discovered Sil1 in three different organisms A conditional lethality screen was used in the yeast Yarrowia lipolytica to detect cellular components that interacted with the 7S RNA or the signal recognition particle SRP during co translational translocation which led to the identification of the Sls1p gene Sls1p is an ER luminal 54 kDa protein that contains an N terminal signal sequence and a C terminal ER retention motif 9 Sls1p fractionated with the membranous fraction and was shown to interact with the Sec61p translocation apparatus Sls1p was induced by ER stresses such as heat shock or inhibition of glycosylation and its deletion resulted in decreased maturation of secretory proteins This protein also bound to the ADP bound form of Kar2p the yeast homolog of BiP and stimulated its interaction with Sec63 a DnaJ family member and a translocon component Disruption of the interaction between Sls1p and Kar2p significantly affected the secretion of a reporter protein leading the investigators to conclude that Sls1p assisted BiP in the translocation of nascent proteins into the ER lumen Another group working with Saccharomyces cerevisiae conducted a screen for genes that would suppress the severe growth defect observed in the DIre1DLhs1 yeast double mutants when overexpressed and named this gene the suppressor of Ire1 and Lhs1 deletion 1 Sil1 Sil1p was shown to be a homolog of Sls1p and a combined deletion of Sil1p and Lhs1 yeast GRP170 proved to be lethal after causing a total block in protein translocation into the ER Mammalian human SIL1 was discovered in a yeast two hybrid screen aimed at identifying proteins that interacted with a mutant ATPase domain of BiP and was initially named BiP associated protein BAP Sequence analysis revealed that BAP is a mammalian homolog of Sls1p and Sil1p and is similar to the cytosolic HSP70 binding protein HSPBP1 Biochemical data further demonstrated that BAP also had NEF activity for BiP Structure and mechanism of nucleotide exchange editStructural data for yeast Sil1p revealed an elongated kidney bean like molecular shape that consists of 16 a helices A1 A16 and lacks b sheets The central helices A3 A14 form the armadillo ARM like repeats ARM1 ARM4 which are named after those found in b catenin Each ARM repeat is composed of three a helices that pack into a superhelix A crystal structure of yeast Sil1p complexed with the ADP bound NBD of Kar2p BiP revealed that the ARM domain of Sil1p wraps around lobe IIb of BiP s NBD and makes additional contacts with lobe Ib This interaction causes lobes Ib and IIb to rotate away from each other leading to ADP release Point mutations in the Sil1p interacting site of Kar2p s NBD specifically disrupted Sil1p binding but retained Kar2p s ability to interact with Lhs1 GRP170 the other ER NEF providing the first indication that their mechanisms of NEF activity were different Homology mapping and comparisons with the structure of cytosolic HSPBP1 indicated that the region of SIL1 encoded by exons 6 and 9 constitutes major BiP binding sites and exon 10 encodes a minor interaction site Tissue expression editAlthough SIL1 is ubiquitously expressed levels vary widely by tissue The Human Protein Atlas www proteinatlas org shows that the expression pattern of SIL1 mirrors that of BiP even more closely than that of GRP170 which is a known UPR target as is BiP Perhaps the different expression pattern for GRP170 is due to its dual function as a chaperone and a NEF for BiP SIL1 expression at a single cell level has also been determined in a number of tissues which does not strictly correlate with the secretory capacity of the cell and tissues displaying the highest relative levels of SIL1 are not necessarily those most affected by loss of its function This might imply an additional function which has been demonstrated for Sil1p or an as yet undiscovered role of SIL1 in certain tissues Understanding this reason for variation in tissue expression will require further studies SIL1IdentifiersAliasesSIL1 BAP MSS ULG5 SIL1 nucleotide exchange factorExternal IDsOMIM 608005 MGI 1932040 HomoloGene 32544 GeneCards SIL1Gene location Human nbsp Chr Chromosome 5 human 1 nbsp nbsp nbsp Band5q31 2Start138 946 724 bp 1 End139 293 557 bp 1 Gene location Mouse nbsp Chr Chromosome 18 mouse 2 nbsp nbsp nbsp Band18 18 B1 B2Start35 399 449 bp 2 End35 632 833 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed inislet of Langerhansbody of pancreasstromal cell of endometriumright adrenal glandleft adrenal glandright lobe of liversural nerveAchilles tendonanterior pituitaryright lobe of thyroid glandTop expressed inspermatocytespermatidlacrimal glandparotid glandseminal vesiculaleft lobe of liverseminiferous tubuleproximal tubuleutriclesupraoptic nucleusMore reference expression dataBioGPS nbsp More reference expression dataGene ontologyMolecular functionunfolded protein binding protein binding adenyl nucleotide exchange factor activityCellular componentendoplasmic reticulum lumen endoplasmic reticulum extracellular space cytoplasmBiological processprotein folding protein transport intracellular protein transport transport regulation of catalytic activitySources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez6437481500EnsemblENSG00000120725ENSMUSG00000024357UniProtQ9H173Q9EPK6RefSeq mRNA NM 001037633NM 022464NM 030749NM 001360814RefSeq protein NP 001032722NP 071909NP 109674NP 001347743Location UCSC Chr 5 138 95 139 29 MbChr 18 35 4 35 63 MbPubMed search 10 11 WikidataView Edit HumanView Edit MouseInteractions editSIL1 has been shown to interact with Binding immunoglobulin protein 6 References edit a b c d e f GRCh38 Ensembl release 89 ENSG00000120725 Ensembl May 2017 a b c d e f GRCm38 Ensembl release 89 ENSMUSG00000024357 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Tyson JR Stirling CJ December 2000 LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum The EMBO Journal 19 23 6440 52 doi 10 1093 emboj 19 23 6440 PMC 305876 PMID 11101517 a b Chung KT Shen Y Hendershot LM December 2002 BAP a mammalian BiP associated protein is a nucleotide exchange factor that regulates the ATPase activity of BiP The Journal of Biological Chemistry 277 49 47557 63 doi 10 1074 jbc M208377200 PMID 12356756 Senderek J Krieger M Stendel C Bergmann C Moser M Breitbach Faller N et al December 2005 Mutations in SIL1 cause Marinesco Sjogren syndrome a cerebellar ataxia with cataract and myopathy Nature Genetics 37 12 1312 4 doi 10 1038 ng1678 PMID 16282977 S2CID 28860307 a b Entrez Gene SIL1 SIL1 homolog endoplasmic reticulum chaperone S cerevisiae Ichhaporia VP Hendershot LM February 2021 Role of the HSP70 Co Chaperone SIL1 in Health and Disease International Journal of Molecular Sciences 22 4 1564 doi 10 3390 ijms22041564 PMC 7913895 PMID 33557244 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Further reading editIchhaporia VP Kim J Kavdia K Vogel P Horner L Frase S Hendershot LM May 2018 SIL1 the endoplasmic reticulum localized BiP co chaperone plays a crucial role in maintaining skeletal muscle proteostasis and physiology Disease Models amp Mechanisms 11 5 dmm033043 doi 10 1242 dmm 033043 PMC 5992605 PMID 29666155 Ichhaporia VP Sanford T Howes J Marion TN Hendershot LM February 2015 Sil1 a nucleotide exchange factor for BiP is not required for antibody assembly or secretion Molecular Biology of the Cell 26 3 420 9 doi 10 1091 mbc E14 09 1392 PMC 4310734 PMID 25473114 Keats B Ott J Conneally M 1989 Report of the committee on linkage and gene order Cytogenetics and Cell Genetics 51 1 4 459 502 doi 10 1159 000132805 PMID 2791656 Clark HF Gurney AL Abaya E Baker K Baldwin D Brush J et al October 2003 The secreted protein discovery initiative SPDI a large scale effort to identify novel human secreted and transmembrane proteins a bioinformatics assessment Genome Research 13 10 2265 70 doi 10 1101 gr 1293003 PMC 403697 PMID 12975309 Lagier Tourenne C Tranebaerg L Chaigne D Gribaa M Dollfus H Silvestri G et al October 2003 Homozygosity mapping of Marinesco Sjogren syndrome to 5q31 European Journal of Human Genetics 11 10 770 8 doi 10 1038 sj ejhg 5201068 PMID 14512967 Colland F Jacq X Trouplin V Mougin C Groizeleau C Hamburger A et al July 2004 Functional proteomics mapping of a human signaling pathway Genome Research 14 7 1324 32 doi 10 1101 gr 2334104 PMC 442148 PMID 15231748 Rual JF Venkatesan K Hao T Hirozane Kishikawa T Dricot A Li N et al October 2005 Towards a proteome scale map of the human protein protein interaction network Nature 437 7062 1173 8 Bibcode 2005Natur 437 1173R doi 10 1038 nature04209 PMID 16189514 S2CID 4427026 Anttonen AK Mahjneh I Hamalainen RH Lagier Tourenne C Kopra O Waris L et al December 2005 The gene disrupted in Marinesco Sjogren syndrome encodes SIL1 an HSPA5 cochaperone Nature Genetics 37 12 1309 11 doi 10 1038 ng1677 PMID 16282978 S2CID 33094308 Otsuki T Ota T Nishikawa T Hayashi K Suzuki Y Yamamoto J et al 2007 Signal sequence and keyword trap in silico for selection of full length human cDNAs encoding secretion or membrane proteins from oligo capped cDNA libraries DNA Research 12 2 117 26 doi 10 1093 dnares 12 2 117 PMID 16303743 Karim MA Parsian AJ Cleves MA Bracey J Elsayed MS Elsobky E Parsian A November 2006 A novel mutation in BAP SIL1 gene causes Marinesco Sjogren syndrome in an extended pedigree Clinical Genetics 70 5 420 3 doi 10 1111 j 1399 0004 2006 00695 x PMID 17026626 S2CID 28527790 External links editGeneReviews NCBI NIH UW entry on Marinesco Sjogren Syndrome nbsp This article on a gene on human chromosome 5 is a stub You can help Wikipedia by expanding it vte Retrieved from https en wikipedia org w index php title SIL1 amp oldid 1116589377, wikipedia, wiki, book, books, library,
