Ivan Belashov- VanDemark Lab
"Uncovering the role of a small adapter protein PEBP1 in ferroptotic cell death mechanism"
Friday, October 16, 2020
12:10 PM
Zoom link:
https://pitt.zoom.us/j/96412260404
Meeting ID: 964 1226 0404
Abstract:
Ferroptosis is an iron-dependent programmed cell death mechanism, which is pervasive, phenotypically distinct from other cell death processes and manifests in poorly-controlled severe types of asthma. One of the key players involved in this mechanism is the phospholipid-binding adaptor protein named PEBP1. Under conditions of prolonged oxidative stress, PEBP1 facilitates the progression of ferroptosis by interacting with lipid-modifying enzymes like 15-lipoxygenase (15LO) and altering their substrate selectivity from generating the essential signaling molecules to instead producing pro-ferroptotic hydroperoxyl-phospholipid conjugates that signal cell death. How PEBP1 governs that switch of substrate selectivity is unknown. Recently, phospholipid PE was identified as one of the most prominent pro-ferroptotic products of 15LO and the initial first-impulse hypothesis was that PEBP1 was directing the ligand selection by delivering PE lipids for their peroxidation in a handoff mechanism. However, despite its historical name as ‘PE-binding protein’, PEBP1 doesn’t appear to bind to PE lipids in vitro. This conundrum prompts the investigation of alternative hypotheses. Currently, our preliminary data suggests that PEBP1 preferentially binds to PA lipids instead of PE. To confirm this, I have performed mutational analyses on PEBP1 to delineate its binding-pocket specificity towards the phospholipid PA. In addition, I am developing new tools to investigate how post-translational modifications may affect the functions of this mysterious adaptor protein.