Structure of the Inhibited State of the Sec Translocon

Gérard, Samuel F., Hall, Belinda S., Zaki, Afroditi M., Corfield, Katherine A., Mayerhofer, Peter U., Costa, Catia, Whelligan, Daniel K., Biggin, Philip C., Simmonds, Rachel E. and Higgins, Matthew K. (2020) Structure of the Inhibited State of the Sec Translocon Molecular Cell, 79 (3). pp. 406-415.

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Abstract

Protein secretion in eukaryotes and prokaryotes involves a universally conserved protein translocation chan-nel formed by the Sec61 complex. Unrelated small-molecule natural products and synthetic compoundsinhibit Sec61 with differential effects for different substrates or for Sec61 from different organisms, makingthis a promising target for therapeutic intervention. To understand the mode of inhibition and provide insightinto the molecular mechanism of this dynamic translocon, we determined the structure of mammalian Sec61inhibited by theMycobacterium ulceransexotoxin mycolactone via electron cryo-microscopy. Unexpect-edly, the conformation of inhibited Sec61 is optimal for substrate engagement, with mycolactone wedgingopen the cytosolic side of the lateral gate. The inability of mycolactone-inhibited Sec61 to effectively trans-port substrate proteins implies that signal peptides and transmembrane domains pass through the site occu-pied by mycolactone. This provides a foundation for understanding the molecular mechanism of Sec61 inhib-itors and reveals novel features of translocon function and dynamics.

Item Type:	Article
Divisions :	Faculty of Engineering and Physical Sciences > Chemistry
Authors :	Name Email ORCID Gérard, Samuel F. Hall, Belinda S. Zaki, Afroditi M. Corfield, Katherine A. Mayerhofer, Peter U. Costa, Catia Whelligan, Daniel K. D.Whelligan@surrey.ac.uk Biggin, Philip C. Simmonds, Rachel E. Higgins, Matthew K.
Date :	6 August 2020
Funders :	Engineering and Physical Sciences Research Council, Wellcome Trust, Joint Academic Data Science Endeavour, Medical Research Council (MRC)
DOI :	10.1016/j.molcel.2020.06.013
Grant Title :	Engineering and Physical Sciences Research Council Grant
Copyright Disclaimer :	ª2020 The Author(s). Published by Elsevier Inc.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Additional Information :	Embargo OK Metadata OK No Further Action
Depositing User :	James Marshall
Date Deposited :	21 Aug 2020 11:22
Last Modified :	21 Aug 2020 11:22
URI:	http://epubs.surrey.ac.uk/id/eprint/858463

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