University of Surrey

Test tubes in the lab Research in the ATI Dance Research

Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone.

McKenna, M, Simmonds, RE and High, S (2016) Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone. Journal of Cell Science, 129.

[img]
Preview
Text (licence)
SRI_deposit_agreement.pdf
Available under License : See the attached licence file.

Download (33kB) | Preview
[img]
Preview
Text
jcs.182352.full.pdf - Version of Record
Available under License : See the attached licence file.

Download (1MB) | Preview

Abstract

The virulence factor mycolactone is responsible for the immunosuppression and tissue necrosis that characterise Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans. In this study, we confirm that Sec61, the protein-conducting channel that coordinates entry of secretory proteins into the endoplasmic reticulum, is a primary target of mycolactone, and characterise the nature of its inhibitory effect. We conclude that mycolactone constrains the ribosome-nascent chain-Sec61 complex, consistent with its broad-ranging perturbation of the co-translational translocation of classical secretory proteins. In contrast, the effect of mycolactone on the post-translational, ribosome-independent translocation of short secretory proteins through the Sec61 complex is dependent on both signal sequence hydrophobicity and the translocation competence of the mature domain. Changes to protease sensitivity strongly suggest that mycolactone acts by inducing a conformational change in the pore-forming Sec61α subunit. These findings establish that mycolactone inhibits Sec61-mediated protein translocation and highlight differences between the co- and post-translational routes that the Sec61 complex mediates. We propose that mycolactone also provides a useful tool for further delineating the molecular mechanisms of Sec61-dependent protein translocation.

Item Type: Article
Subjects : Biosciences
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :
AuthorsEmailORCID
McKenna, MUNSPECIFIEDUNSPECIFIED
Simmonds, REUNSPECIFIEDUNSPECIFIED
High, SUNSPECIFIEDUNSPECIFIED
Date : 1 April 2016
Funders : Biotechnology and Biological Sciences Research Council, Wellcome Trust
Identification Number : 10.1242/jcs.182352
Copyright Disclaimer : © 2016. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
Uncontrolled Keywords : Buruli ulcer, Endoplasmic reticulum, Mycobacterium ulcerans, Mycolactone, Sec61, Short secretory protein
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 22 Jul 2016 08:44
Last Modified : 22 Jul 2016 08:44
URI: http://epubs.surrey.ac.uk/id/eprint/810048

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year


Information about this web site

© The University of Surrey, Guildford, Surrey, GU2 7XH, United Kingdom.
+44 (0)1483 300800