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Secretory protein profiling reveals TNF-? inactivation by selective and promiscuous Sec61 modulators.


ABSTRACT: Cotransins are cyclic heptadepsipeptides that bind the Sec61 translocon to inhibit cotranslational translocation of a subset of secreted and type I transmembrane proteins. The few known cotransin-sensitive substrates are all targeted to the translocon by a cleavable signal sequence, previously shown to be a critical determinant of cotransin sensitivity. By profiling two cotransin variants against a panel of secreted and transmembrane proteins, we demonstrate that cotransin side-chain differences profoundly affect substrate selectivity. Among the most sensitive substrates we identified is the proinflammatory cytokine tumor necrosis factor alpha (TNF-?). Like all type II transmembrane proteins, TNF-? is targeted to the translocon by its membrane-spanning domain, indicating that a cleavable signal sequence is not strictly required for cotransin sensitivity. Our results thus reveal an unanticipated breadth of translocon substrates whose expression is inhibited by Sec61 modulators.

SUBMITTER: Maifeld SV 

PROVIDER: S-EPMC3855466 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Secretory protein profiling reveals TNF-α inactivation by selective and promiscuous Sec61 modulators.

Maifeld Sarah V SV   MacKinnon Andrew L AL   Garrison Jennifer L JL   Sharma Ajay A   Kunkel Eric J EJ   Hegde Ramanujan S RS   Taunton Jack J  

Chemistry & biology 20110901 9


Cotransins are cyclic heptadepsipeptides that bind the Sec61 translocon to inhibit cotranslational translocation of a subset of secreted and type I transmembrane proteins. The few known cotransin-sensitive substrates are all targeted to the translocon by a cleavable signal sequence, previously shown to be a critical determinant of cotransin sensitivity. By profiling two cotransin variants against a panel of secreted and transmembrane proteins, we demonstrate that cotransin side-chain differences  ...[more]

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