Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.

Translocation of secretory and integral membrane proteins across or into the ER membrane occurs via the Sec61 complex, a heterotrimeric protein complex possessing two essential sub-units, Sec61p/Sec61α and Sss1p/Sec61γ and the non-essential Sbh1p/Sec61β subunit. In addition to forming a protein cond...

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Autores principales:	Christopher M Witham, Aleshanee L Paxman, Lamprini Baklous, Robert F L Steuart, Benjamin L Schulz, Carl J Mousley
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/1017cb428036497fb1393b41215a322f
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spelling	oai:doaj.org-article:1017cb428036497fb1393b41215a322f2021-12-02T20:02:50ZCancer associated mutations in Sec61γ alter the permeability of the ER translocase.1553-73901553-740410.1371/journal.pgen.1009780https://doaj.org/article/1017cb428036497fb1393b41215a322f2021-08-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009780https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Translocation of secretory and integral membrane proteins across or into the ER membrane occurs via the Sec61 complex, a heterotrimeric protein complex possessing two essential sub-units, Sec61p/Sec61α and Sss1p/Sec61γ and the non-essential Sbh1p/Sec61β subunit. In addition to forming a protein conducting channel, the Sec61 complex maintains the ER permeability barrier, preventing flow of molecules and ions. Loss of Sec61 integrity is detrimental and implicated in the progression of disease. The Sss1p/Sec61γ C-terminus is juxtaposed to the key gating module of Sec61p/Sec61α and is important for gating the translocon. Inspection of the cancer genome database identifies six mutations in highly conserved amino acids of Sec61γ/Sss1p. We identify that five out of the six mutations identified affect gating of the ER translocon, albeit with varying strength. Together, we find that mutations in Sec61γ that arise in malignant cells result in altered translocon gating dynamics, this offers the potential for the translocon to represent a target in co-therapy for cancer treatment.Christopher M WithamAleshanee L PaxmanLamprini BaklousRobert F L SteuartBenjamin L SchulzCarl J MousleyPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 8, p e1009780 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Christopher M Witham Aleshanee L Paxman Lamprini Baklous Robert F L Steuart Benjamin L Schulz Carl J Mousley Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.
description	Translocation of secretory and integral membrane proteins across or into the ER membrane occurs via the Sec61 complex, a heterotrimeric protein complex possessing two essential sub-units, Sec61p/Sec61α and Sss1p/Sec61γ and the non-essential Sbh1p/Sec61β subunit. In addition to forming a protein conducting channel, the Sec61 complex maintains the ER permeability barrier, preventing flow of molecules and ions. Loss of Sec61 integrity is detrimental and implicated in the progression of disease. The Sss1p/Sec61γ C-terminus is juxtaposed to the key gating module of Sec61p/Sec61α and is important for gating the translocon. Inspection of the cancer genome database identifies six mutations in highly conserved amino acids of Sec61γ/Sss1p. We identify that five out of the six mutations identified affect gating of the ER translocon, albeit with varying strength. Together, we find that mutations in Sec61γ that arise in malignant cells result in altered translocon gating dynamics, this offers the potential for the translocon to represent a target in co-therapy for cancer treatment.
format	article
author	Christopher M Witham Aleshanee L Paxman Lamprini Baklous Robert F L Steuart Benjamin L Schulz Carl J Mousley
author_facet	Christopher M Witham Aleshanee L Paxman Lamprini Baklous Robert F L Steuart Benjamin L Schulz Carl J Mousley
author_sort	Christopher M Witham
title	Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.
title_short	Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.
title_full	Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.
title_fullStr	Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.
title_full_unstemmed	Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.
title_sort	cancer associated mutations in sec61γ alter the permeability of the er translocase.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/1017cb428036497fb1393b41215a322f
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Cancer associated mutations in Sec61γ alter the permeability of the ER translocase.

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