When
Where
Presenter:
Dr. Smriti Sangwan
Dr. Smirti Sangwan
Abstract:
Protein folding is essential for cellular health. Cells employ dedicated machineries comprised of transcriptional, co-translational and post-translational mechanisms to ensure all proteins are correctly folded. My research focuses on understanding the molecular mechanisms of co-translational quality control. Specifically, I have focused on two proteins: IRE1 and eIF2A. IRE1 acts as a gatekeeper of the ER, the site of folding of most transmembrane and secreted proteins. It senses the accumulation of unfolded proteins in the ER and issues corrective action by cleaving ER-localized mRNAs thus reducing translational load on the ER. How IRE1 senses mRNAs in proximity for cleavage is currently unknown. Using biochemical assays, single particle cryoEM and next-generation sequencing I discovered that under basal conditions, IRE1 interacts with the translation machinery primed to cleave mRNAs upon activation. In another project, I focused on eIF2A, an initiation factor involved in the translation of select mRNAs under stress. Its role and mechanism of action have been completely unknown. I determined the structure of eIF2A bound to 40S ribosomal subunits. eIF2A binds at the P-site tethered to the 40S via its C-terminal unstructured region. Removal of the C-terminal region prevents binding to 40S and renders eIF2A inactive in translation under any context. My work provides structural and functional insights into the role of IRE1 and eIF2A in translation and underscores the importance of translation as a hub for protein quality control.