Cancer associated mutations in Sec61[gamma] alter the permeability of the ER translocase

• Published in: PLoS genetics 2021-08, Vol.17 (8)
• Main Authors: Witham, Christopher M, Paxman, Aleshanee L, Baklous, Lamprini, Steuart, Robert F. L, Schulz, Benjamin L, Mousley, Carl J
• Format: Article
• Language: English
• Subjects: Cancer; Endoplasmic reticulum; Genetic aspects; Genetic research; Health aspects; Membrane proteins; Mutation (Biology); Oncology, Experimental; Physiological aspects
• ISSN: 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1009780

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/Sec61[alpha] and Sss1p/Sec61[gamma] and the non-essential Sbh1p/Sec61[beta] 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/Sec61[gamma] C-terminus is juxtaposed to the key gating module of Sec61p/Sec61[alpha] and is important for gating the translocon. Inspection of the cancer genome database identifies six mutations in highly conserved amino acids of Sec61[gamma]/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 Sec61[gamma] 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.