Allosteric Autoregulation of Ferroptosis Suppressor Protein 1 Activity by its N-myristoylated Tail

Ferroptosis is a form of cell death characterized by iron-dependent accumulation of lipid peroxides. Ferroptosis suppressor protein 1 (FSP1) has been shown to work with glutathione peroxidase 4 (GPX4) to suppress ferroptosis through different antioxidant pathways. Many studies have been conducted on FSP1 to better understand its function and mechanism of action, which remained inconclusive in the absence of structural information on FSP1. Recent elucidation of FSP1 structures in different forms and advances in computational characterization of functional changes in its conformation provide us with the opportunity of dissecting FSP1 mechanism of action and gaining insights into critical sites and interactions that control its activity. We present the results from elastic network model analyses of cooperative changes in FSP1 structure, as well as those from molecular dynamics simulations of its interactions with the lipid bilayer and small molecules, toward assisting in future development of modulators of ferroptosis targeting FSP1. Our study reveals the critical role of N-terminal myristoylated tail in modulating the accessibility of the ligand-binding sites and in anchoring FSP1 to the membrane, giving insights into mechanisms of regulating FSP1 function.