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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\u2013nascent-chain\u2013Sec61 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 Sec61\u03b1 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.<\/jats:p>","DOI":"10.1242\/jcs.182352","type":"journal-article","created":{"date-parts":[[2016,2,12]],"date-time":"2016-02-12T03:43:33Z","timestamp":1455248613000},"page":"1404-1415","source":"Crossref","is-referenced-by-count":110,"title":["Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone"],"prefix":"10.1242","volume":"129","author":[{"given":"Michael","family":"McKenna","sequence":"first","affiliation":[{"name":"University of Manchester 1 Faculty of Life Sciences , , Michael Smith Building, Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel E.","family":"Simmonds","sequence":"additional","affiliation":[{"name":"School of Bioscience and Medicine 2 Department of Microbial Sciences , , Faculty of Health and Medical Sciences , , Guildford GU2 7XH , UK"},{"name":"University of Surrey 2 Department of Microbial Sciences , , Faculty of Health and Medical Sciences , , Guildford GU2 7XH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"High","sequence":"additional","affiliation":[{"name":"University of Manchester 1 Faculty of Life Sciences , , Michael Smith Building, Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2024061316075632900_JCS182352C1","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1038\/sj.emboj.7600281","article-title":"Signal recognition particle mediates post-translational targeting in eukaryotes","volume":"23","author":"Abell","year":"2004","journal-title":"EMBO J."},{"key":"2024061316075632900_JCS182352C2","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/0042-6989(91)90069-H","article-title":"Anti-rhodopsin monoclonal antibodies of defined specificity: characterization and application","volume":"31","author":"Adamus","year":"1991","journal-title":"Vision Res."},{"key":"2024061316075632900_JCS182352C3","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1126\/science.1178535","article-title":"Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome","volume":"326","author":"Becker","year":"2009","journal-title":"Science"},{"key":"2024061316075632900_JCS182352C4","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1038\/nature03670","article-title":"Selective inhibition of cotranslational translocation of vascular cell adhesion molecule 1","volume":"436","author":"Besemer","year":"2005","journal-title":"Nature"},{"key":"2024061316075632900_JCS182352C5","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1083\/jcb.67.3.835","article-title":"Transfer of proteins across membranes. 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