Cancer associated mutations in Sec61γ alter the permeability of the ER translocase
| Autor: | Lamprini Baklous, Christopher M. Witham, Carl J. Mousley, Benjamin L. Schulz, Aleshanee L. Paxman, Robert F. L. Steuart |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Cell Membrane Permeability Gating QH426-470 Endoplasmic Reticulum medicine.disease_cause Lung and Intrathoracic Tumors Database and Informatics Methods Neoplasms Heterotrimeric G protein Medicine and Health Sciences Translocase Integral membrane protein Genetics (clinical) Mutation Secretory Pathway biology Eukaryota Genomics Genomic Databases Translocon Cell biology Protein Transport Oncology Cell Processes Nephrology Renal Cancer Physical Sciences Cellular Structures and Organelles Research Article Sec61 Saccharomyces cerevisiae Proteins Materials Science Material Properties Saccharomyces cerevisiae Research and Analysis Methods Permeability Genetics medicine Amino Acid Sequence Molecular Biology Ecology Evolution Behavior and Systematics Endoplasmic reticulum Organisms Fungi Biology and Life Sciences Cancers and Neoplasms Computational Biology Membrane Proteins Membrane Transport Proteins Biological Transport Cell Biology Genome Analysis Yeast Biological Databases Mutation Databases biology.protein SEC Translocation Channels |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 17, Iss 8, p e1009780 (2021) |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1009780 |
| Popis: | 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. 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/Sec61α, Sbh1p/Sec61β and Sss1p/Sec61γ. 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 Sec61γ 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|