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Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase

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Show simple item record Greenblatt, Wesley H. Rubenstein, Eric M. Kreft, Stefan G. Swanson, Robert Hochstrasser, Mark 2012-11-16T20:11:38Z 2012-11-16T20:11:38Z 2012-06 2012-03
dc.identifier.issn 0021-9525
dc.identifier.issn 1540-8140
dc.description.abstract Little is known about quality control of proteins that aberrantly or persistently engage the endoplasmic reticulum (ER)-localized translocon en route to membrane localization or the secretory pathway. Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets of misfolded or otherwise abnormal proteins based primarily on degradation signal (degron) location. We report the surprising observation that fusing Deg1, a cytoplasmic degron normally recognized by Doa10, to the Sec62 membrane protein rendered the protein a Hrd1 substrate. Hrd1-dependent degradation occurred when Deg1-Sec62 aberrantly engaged the Sec61 translocon channel and underwent topological rearrangement. Mutations that prevent translocon engagement caused a reversion to Doa10-dependent degradation. Similarly, a variant of apolipoprotein B, a protein known to be cotranslocationally targeted for proteasomal degradation, was also a Hrd1 substrate. Hrd1 therefore likely plays a general role in targeting proteins that persistently associate with and potentially obstruct the translocon. en_US
dc.language.iso en_US
dc.publisher Rockefeller University Press, The en_US
dc.relation.isversionof en_US
dc.rights Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported en_US
dc.rights.uri en_US
dc.source Rockefeller UP en_US
dc.title Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase en_US
dc.type Article en_US
dc.identifier.citation Rubenstein, E. M. et al. “Aberrant Substrate Engagement of the ER Translocon Triggers Degradation by the Hrd1 Ubiquitin Ligase.” The Journal of Cell Biology 197.6 (2012): 761–773. © 2012 by The Rockefeller University Press en_US
dc.contributor.department Harvard University--MIT Division of Health Sciences and Technology en_US
dc.contributor.mitauthor Greenblatt, Wesley H.
dc.relation.journal Journal of Cell Biology en_US
dc.identifier.mitlicense PUBLISHER_CC en_US
dc.eprint.version Final published version en_US
dc.type.uri en_US
eprint.status en_US
dspace.orderedauthors Rubenstein, E. M.; Kreft, S. G.; Greenblatt, W.; Swanson, R.; Hochstrasser, M. en

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