Role of Dynamics in the Structure and Function of Intrinsically Metastable Proteins

Type of Award: Catalyst
Date Awarded: February 2015
Award End Date: January 2017
Amount Awarded: $ 200,000.00
PI(s): Michael Caffrey, PhD, UIC; Arnon Lavie, PhD, UIC; Balaji Manicassamy, PhD, UChicago;

Abstract: Many proteins function as nanomachines in which conformational changes are prerequisite for their function. Classic examples include myosin-actin in muscle contraction, ATP synthase for ATP generation and active transport, G-Protein Coupled Receptors that relay extracellular signals (GPCR, and the family of proteins that mediate fusion of biological membranes, which are the focus of this proposal. In each of the above cases, an external trigger leads to an alternative conformation relative to the intrinsically metastable (IM) pre-trigger state. Not surprisingly, maintenance of this IM conformation is highly regulated and its destabilization or stabilization may disrupt fundamental biological pathways. Whereas disruption of the IM state often leads to disease, we propose that this vulnerability can be exploited for therapeutic purposes. In this work we have chosen as model system the well-characterized examples of IM proteins that mediate virus fusion with the host cell, a key step in virus infectivity. We hypothesize that local dynamic motions determine the propensity of the IM state transitioning to the alternative stable conformation. Additionally, we suggest that stabilizing or destabilizing mutations, or small molecule agonists or antagonists, can disrupt conformational changes, and function, by altering local dynamics.