Cancer Associated Mutations In Sec61 Gamma 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/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.Author summary The first step in the biogenesis of secretory proteins is the targeting and translocation into the endoplasmic reticulum (ER). Secretory proteins enter the ER via a gated channel in the ER membrane called the translocon, a protein complex composed of Sec61p/Sec61 alpha, Sbh1p/Sec61 beta and Sss1p/Sec61 gamma. As a protein conducting channel the translocon must be sealed in a regulated manner to prevent the free flow of ions and small molecules between the ER and cytosol. We have discovered that mutations in Sec61 gamma that arise in cancer affect this seal but not the ability of this protein complex to translocate secretory proteins into the ER. We hypothesise that altered translocon gating contributes to malignancy by influencing factors such as migration, autophagy and chemotherapy resistance.