Towards a Structural Basis for Argininosuccinate synthetase (ASS1) Regulation
Lucky Gurung, Jeanan Ahmad, Danya Abdallah, Jerrade Domingo, Michelle Von Merta-Sustarich, Ryan Leung
Department of Chemistry & Biochemistry
Faculty Supervisor: Eric Greene
Argininosuccinate synthetase (ASS1) catalyzes a key step in both arginine biosynthesis and the urea cycle and is subject to activity regulation at the protein level. Multiple studies suggest that ASS1 activity can be modulated by distinct protein effectors and chemical modifications, including interactions with NMRAL1, the Bj-BPP-10c peptide, circadian regulator–associated with post-translational modifications, and cysteine nitrosylation. While these findings suggest diverse activation and inhibition mechanisms, the structural and conformational basis of such regulation remain unknown. We propose to use a combination of steady-state enzymology, mutagenesis, and cryo-electron microscopy, to determine how these modulators reshape the ASS1 conformational landscape. Our initial studies indicate substrate-induced conformational changes, and our primary goal is to determine how protein-protein interactions and modifications further modulate enzyme conformation and catalysis. Defining these mechanisms will provide insight into metabolic control and may identify new opportunities for therapeutic intervention in nitrogen metabolism.