Michelle Arkin, PhD, University of California San Francisco, Webinar

Moderator: Michelle Arkin, PhD, Professor and Chair, Department of Pharmaceutical Chemistry, UCSF

Webinar title: Molecular glues for 14-3-3sigma/CRAF as potential probes and drugs for Noonan’s Syndrome

Abstract: 14‑3‑3 is a hub protein that interacts with hundreds of client proteins. One 14-3-3 client is CRAF and binds to CRAF pS259 to prevent its activation and MAPK signaling. Mutations around S259 (CRAFNS) cause the developmental disease Noonan syndrome, resulting in an impaired interaction. Noonan mutations decreased the level of pS259 by 64-97% compared to CRAFWT. CRAFNS peptides have a 2- to over 12-fold decrease in affinity to 14-3-3 compared to CRAFWT. The Arkin lab aims to develop stabilizers of protein-protein interactions (PPIs) to enhance the binding affinity of weakened interactions in disease. The Arkin lab has developed stabilizers of the 14-3-3/CRAFWT interaction that stabilize the 14-3-3/CRAFNS interactions to varying degrees (2 to >100x), depending on whether the mutation lies N-or C-terminal to S259, and strengthen the levels of pS259 up to 4.6-fold. Due to the proximity of the C-terminal mutants to the compound binding site, a site-directed disulfide tethering screen for mutant-specific stabilizers has been conducted to identify molecular glues that selectively stabilize these mutations over WT. The results from this project will elucidate the biochemical and cellular effects of modulating weakened PPIs through molecular glues and could reveal a novel therapeutic strategy for Noonan syndrome.

Presenter: Johanna Virta: Johanna Virta is a fourth-year PhD student in the Arkin lab at University of California, San Francisco. Her thesis work focuses on drug discovery for stabilization of protein-protein interactions in the rare disease Noonan Syndrome. Stabilization of the 14-3-3/CRAF interaction in Noonan Syndrome provides insight into the mechanisms underlying this rare disease and a novel therapeutic opportunity. Prior to UCSF, Johanna worked in the lab of Sam Butcher at the University of Wisconsin, Madison as an undergraduate researcher and a post-baccalaureate studying RNA-binding proteins involved in RNA decay.