Carol Post

Borch Department of Medicinal Chemistry and Molecular Pharmacology and Department of Biological Sciences, Purdue University, West Lafayette, IN, USA - Research

Phosphorylation influence on protein conformational equilibrium with connections to functional outcomes

Abstract

The function of multidomain proteins such as those in cellular signaling is often regulated by post‑translational phosphorylation. The localization of proteins within cells as well as the levels of enzymatic activity are both tightly controlled to output the proper functionality. One component of regulation is the control of inter‑domain structure through phosphorylation. To best understand these fundamental processes, we scrutinized conformational behavior of µs‑timescale molecular dynamics simulations in concert with NMR relaxation to gain insight into the physical basis of responses to phosphorylation. Analyses elucidated regulation mechanisms of protein-protein interactions relevant to localization. This talk will explain an entropy-driven phospho-sensor so far unique to Syk tyrosine kinase. We discovered a network of interactions that includes a central triad of charged residues that switches salt‑bridge partners in response to phosphorylation. We envision the design of biosensors derived from principles of the Syk network. In addition, how linker phosphorylation of FAK-FERM kinase alters linker dynamics to enable protein‑protein interactions critical for coordinating cellular events underlying cell adhesion and migration will be presented. Given the disease relevance of both Syk and FAK kinases, knowledge on functional regulation by phosphorylation is projected to inform future drug development efforts.