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The skin lesions and immunosuppression that are characteristic of this disease result from the action of mycolactone, which targets the Sec61 complex and inhibits the co-translational translocation of secretory proteins into the endoplasmic reticulum. In this study, we investigate the effect of mycolactone on the Sec61-dependent biogenesis of different classes of transmembrane protein (TMP). Our data suggest that the effect of mycolactone on TMP biogenesis depends on how the nascent chain initially engages the Sec61 complex. For example, the translocation of TMP lumenal domains driven by an N-terminal cleavable signal sequence is efficiently inhibited by mycolactone. In contrast, the effect of mycolactone on protein translocation that is driven solely by a non-cleavable signal anchor\/transmembrane domain depends on which flanking region is translocated. For example, while translocation of the region N-terminal to a signal anchor\/transmembrane domain is refractive to mycolactone, C-terminal translocation is efficiently inhibited. Our findings highlight the diversity of Sec61-dependent translocation and provide a molecular basis for understanding the effect of mycolactone on the biogenesis of different TMPs.<\/jats:p>","DOI":"10.1242\/jcs.198655","type":"journal-article","created":{"date-parts":[[2017,2,21]],"date-time":"2017-02-21T01:20:18Z","timestamp":1487640018000},"page":"1307-1320","source":"Crossref","is-referenced-by-count":78,"title":["Mycolactone reveals the substrate-driven complexity of Sec61-dependent transmembrane protein biogenesis"],"prefix":"10.1242","volume":"130","author":[{"given":"Michael","family":"McKenna","sequence":"first","affiliation":[{"name":"School of Biological Sciences 1 Division of Molecular and Cellular Function , , Faculty of Biology , , Michael Smith Building, Manchester M13 9PT , UK"},{"name":"Medicine and Health, University of Manchester, Manchester Academic Health Science Centre 1 Division of Molecular and Cellular Function , , Faculty of Biology , , 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4532-8152","authenticated-orcid":false,"given":"Stephen","family":"High","sequence":"additional","affiliation":[{"name":"School of Biological Sciences 1 Division of Molecular and Cellular Function , , Faculty of Biology , , Michael Smith Building, Manchester M13 9PT , UK"},{"name":"Medicine and Health, University of Manchester, Manchester Academic Health Science Centre 1 Division of Molecular and Cellular Function , , Faculty of Biology , , Michael Smith Building, Manchester M13 9PT , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2024061316410483100_JCS198655C1","doi-asserted-by":"publisher","first-page":"2885","DOI":"10.1084\/jem.20160662","article-title":"Mycolactone subverts immunity by selectively blocking the Sec61 translocon","volume":"213","author":"Baron","year":"2016","journal-title":"J. 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