Co-chaperone Specificity in Gating of the Polypeptide Conducting Channel in the Membrane of the Human Endoplasmic Reticulum

DC FieldValueLanguage
dc.contributor.authorSchorr, Stefan
dc.contributor.authorKlein, Marie-Christine
dc.contributor.authorGamayun, Igor
dc.contributor.authorMelnyk, Armin
dc.contributor.authorJung, Martin
dc.contributor.authorSchaeuble, Nico
dc.contributor.authorWang, Qian
dc.contributor.authorHemmis, Birgit
dc.contributor.authorBochen, Florian
dc.contributor.authorGreiner, Markus
dc.contributor.authorLampel, Pavel
dc.contributor.authorUrban, Sabine Katharina
dc.contributor.authorHassdenteufel, Sarah
dc.contributor.authorDudek, Johanna
dc.contributor.authorChen, Xing-Zhen
dc.contributor.authorWagner, Richard
dc.contributor.authorCavalie, Adolfo
dc.contributor.authorZimmermann, Richard
dc.date.accessioned2021-12-23T16:16:18Z-
dc.date.available2021-12-23T16:16:18Z-
dc.date.issued2015
dc.identifier.urihttps://osnascholar.ub.uni-osnabrueck.de/handle/unios/11807-
dc.description.abstractIn mammalian cells, signal peptide-dependent protein transport into the endoplasmic reticulum (ER) is mediated by a dynamic polypeptide-conducting channel, the heterotrimeric Sec61 complex. Previous work has characterized the Sec61 complex as a potential ER Ca2+ leak channel in HeLa cells and identified ER lumenal molecular chaper one immunoglobulin heavy-chain-binding protein (BiP) as limiting Ca2+ leakage via the open Sec61 channel by facilitating channel closing. This BiP activity involves binding of BiP to the ER lumenal loop 7 of Sec61 alpha in the vicinity of tyrosine 344. Of note, the Y344H mutation destroys the BiP binding site and causes pancreatic alpha-cell apoptosis and diabetes in mice. Here, we systematically depleted HeLa cells of the BiP co-chaperones by siRNA-mediated gene silencing and used live cell Ca2+ imaging to monitor the effects on ER Ca2+ leakage. Depletion of either one of the ER lumenal BiP co-chaperones, ERj3 and ERj6, but not the ER membrane-resident co-chaperones (such as Sec63 protein, which assists BiP in Sec61 channel opening) led to increased Ca2+ leakage via Sec6 complex, thereby phenocopying the effect of BiP depletion. Thus, BiP facilitates Sec61 channel closure (i.e. limits ER Ca2+ leakage) via the Sec61 channel with the help of ERj3 and ERj6. Interestingly, deletion of ERj6 causes pancreatic beta-cell failure and diabetes in mice and humans. We suggest that co-chaperone-controlled gating of the Sec61 channel by BiP is particularly important for cells, which are highly active in protein secretion, and that breakdown of this regulatory mechanism can cause apoptosis and disease.
dc.description.sponsorshipDeutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [FOR 967, IRTG 1830, SFB 894]; HOMFOR; This work was supported by Deutsche Forschungsgemeinschaft Grants FOR 967, IRTG 1830, and SFB 894 and by a HOMFOR grant (to M. J.). The authors declare that they have no conflicts of interest with the contents of this article.
dc.language.isoen
dc.publisherAMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.relation.ispartofJOURNAL OF BIOLOGICAL CHEMISTRY
dc.subjectBiochemistry & Molecular Biology
dc.subjectBIP
dc.subjectCA2+ LEAK
dc.subjectCALCIUM LEAK
dc.subjectDIABETES-MELLITUS
dc.subjectDNAJ HOMOLOG
dc.subjectINTRACELLULAR CA2+
dc.subjectSEC61 TRANSLOCON
dc.subjectSECRETORY PROTEINS
dc.subjectSTRESS
dc.subjectUNFOLDED PROTEIN RESPONSE
dc.titleCo-chaperone Specificity in Gating of the Polypeptide Conducting Channel in the Membrane of the Human Endoplasmic Reticulum
dc.typejournal article
dc.identifier.doi10.1074/jbc.M115.636639
dc.identifier.isiISI:000358512100032
dc.description.volume290
dc.description.issue30
dc.description.startpage18621
dc.description.endpage18635
dc.contributor.orcid0000-0002-1482-7020
dc.contributor.orcid0000-0002-1482-7020
dc.contributor.orcid0000-0002-1210-980X
dc.contributor.researcheridD-2207-2012
dc.contributor.researcheridAAM-4547-2021
dc.identifier.eissn1083351X
dc.publisher.place9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
dcterms.isPartOf.abbreviationJ. Biol. Chem.
dcterms.oaStatusGreen Published, hybrid
crisitem.author.deptFB 03 - Erziehungs- und Kulturwissenschaften-
crisitem.author.deptFB 05 - Biologie/Chemie-
crisitem.author.deptidfb03-
crisitem.author.deptidfb05-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.parentorgUniversität Osnabrück-
crisitem.author.netidJuMa702-
crisitem.author.netidWaRi703-
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