UROP Research Mentor Project Submission Portal: Submission #1242

Overall Research Project Description α-Actinin2, encoded by ACTN2, is a key cross-linker of F-actin and titin within cardiac Z-discs, maintaining sarcomere architecture and mechanical integrity. Phosphoproteomic studies have identified multiple phosphorylation sites—including T43, S50, S147, and T237 in the actin-binding domain (ABD)—that likely regulate its function. Mechanical stress enhances phosphorylation at these residues, particularly within the ABD CH1–CH2 interface, which we have shown in computational simulations shifts the ABD from a closed to an open, more active conformation. Phosphorylation introduces negative charges that modulate local electrostatics, destabilize the autoinhibited state, and enhance F-actin binding. This project will experimentally test how these modifications alter α-actinin2 conformation using SAXS, aiming to define the molecular mechanisms by which phosphorylation preserves sarcomeric integrity and informs therapeutic strategies for heart disease.