A substrate-specific inhibitor of protein translocation into the endoplasmic reticulum

Jennifer L. Garrison, Eric J. Kunkel, Ramanujan S. Hegde () and Jack Taunton ()
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Jennifer L. Garrison: University of California
Eric J. Kunkel: Bioseek, Inc.
Ramanujan S. Hegde: National Institutes of Health
Jack Taunton: University of California

Nature, 2005, vol. 436, issue 7048, 285-289

Abstract: Abstract The segregation of secretory and membrane proteins to the mammalian endoplasmic reticulum is mediated by remarkably diverse signal sequences that have little or no homology with each other1,2. Despite such sequence diversity, these signals are all recognized and interpreted by a highly conserved protein-conducting channel composed of the Sec61 complex3,4. Signal recognition by Sec61 is essential for productive insertion of the nascent polypeptide into the translocation site5, channel gating6 and initiation of transport. Although subtle differences in these steps can be detected between different substrates7,8, it is not known whether they can be exploited to modulate protein translocation selectively. Here we describe cotransin, a small molecule that inhibits protein translocation into the endoplasmic reticulum. Cotransin acts in a signal-sequence-discriminatory manner to prevent the stable insertion of select nascent chains into the Sec61 translocation channel. Thus, the range of substrates accommodated by the channel can be specifically and reversibly modulated by a cell-permeable small molecule that alters the interaction between signal sequences and the Sec61 complex.

Date: 2005
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DOI: 10.1038/nature03821

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