Structure of the Inhibited State of the Sec Translocon

Molecular Cell
Samuel F GérardMatthew K Higgins

Abstract

Protein secretion in eukaryotes and prokaryotes involves a universally conserved protein translocation channel formed by the Sec61 complex. Unrelated small-molecule natural products and synthetic compounds inhibit Sec61 with differential effects for different substrates or for Sec61 from different organisms, making this a promising target for therapeutic intervention. To understand the mode of inhibition and provide insight into the molecular mechanism of this dynamic translocon, we determined the structure of mammalian Sec61 inhibited by the Mycobacterium ulcerans exotoxin mycolactone via electron cryo-microscopy. Unexpectedly, the conformation of inhibited Sec61 is optimal for substrate engagement, with mycolactone wedging open the cytosolic side of the lateral gate. The inability of mycolactone-inhibited Sec61 to effectively transport substrate proteins implies that signal peptides and transmembrane domains pass through the site occupied by mycolactone. This provides a foundation for understanding the molecular mechanism of Sec61 inhibitors and reveals novel features of translocon function and dynamics.

References

Jan 1, 1983·Methods in Enzymology·P Walter, G Blobel
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Mar 1, 1985·Physical Review A: General Physics·W G Hoover
Feb 15, 2002·Organic Letters·Fengbin SongYoshito Kishi
Dec 9, 2003·Nature·Bert Van den BergTom A Rapoport
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
May 26, 2005·Bioinformatics·Liskin Swint-Kruse, Curties S Brown
Sep 15, 2005·Journal of Bacteriology·Margaret A SmithAnn M Flower
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Sep 12, 2006·Journal of Structural Biology·Thomas D GoddardThomas E Ferrin
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
Mar 21, 2007·Methods : a Companion to Methods in Enzymology·Christian KandtD Peter Tieleman
Sep 26, 2007·The Journal of Biological Chemistry·Tina JunneMartin Spiess
Nov 7, 2007·Journal of the American Chemical Society·Andrew L MacKinnonJack Taunton
Nov 12, 2009·Journal of Cell Science·Benedict C S CrossEileithyia Swanton
Nov 20, 2009·Nature·Giorgos GouridisAnastassios Economou
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 22, 2010·Proteins·Kresten Lindorff-LarsenDavid E Shaw
Apr 19, 2011·Journal of Computational Chemistry·Naveen Michaud-AgrawalOliver Beckstein
Feb 23, 2012·The Journal of Physical Chemistry. B·Joakim P M Jämbeck, Alexander P Lyubartsev
Jul 31, 2012·Nature Methods·Sjors H W Scheres, Shaoxia Chen
Aug 21, 2012·Journal of Structural Biology·Dominika Elmlund, Hans Elmlund
Sep 25, 2012·Journal of Structural Biology·Sjors H W Scheres
Dec 12, 2012·The Journal of Cell Biology·Steven F TruemanReid Gilmore
Jun 17, 2014·Cell·Rebecca M VoorheesRamanujan S Hegde
Aug 19, 2015·Journal of Structural Biology·Alexis Rohou, Nikolaus Grigorieff
Jan 8, 2013·Journal of Chemical Theory and Computation·Joakim P M Jämbeck, Alexander P Lyubartsev
Aug 14, 2012·Journal of Chemical Theory and Computation·Joakim P M Jämbeck, Alexander P Lyubartsev
Jan 1, 2008·Journal of Chemical Theory and Computation·Berk Hess
Jan 2, 2016·Science·Rebecca M Voorhees, Ramanujan S Hegde
May 9, 2016·Current Opinion in Cell Biology·Rebecca M Voorhees, Ramanujan S Hegde
May 21, 2016·Cell Chemical Biology·Anja O PaateroVille O Paavilainen
Nov 9, 2016·The Journal of Experimental Medicine·Ludivine BaronCaroline Demangel
Jan 12, 2017·Journal of Computer-aided Molecular Design·Kai LiuHironori Kokubo

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Citations

Feb 20, 2021·Immunological Reviews·Caroline Demangel
Apr 19, 2021·Trends in Cell Biology·Madeline M DavisBarry D Bruce
Jun 4, 2021·Scientific Reports·Peristera RobotiStephen High
May 8, 2021·The FEBS Journal·Sarah O'KeefeStephen High
Dec 3, 2020·The Journal of Organic Chemistry·Guanghui ZongWei Q Shi
Aug 31, 2021·PLoS Genetics·Christopher M WithamCarl J Mousley

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Datasets Mentioned

BETA
NA934

Methods Mentioned

BETA
electron microscopy
electron cryo-microscopy
PCR

Software Mentioned

GraphPad Prism
ChimeraX
Chimera
MotionCor2
BLASTn
Relion3
MDAnalysis
CTFFIND4
COOT
EPU

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