Investigating the Role of Interfacial Residues in Mediating the Interdomain Allostery of Hsp70

Abstract

The heat shock protein 70 (Hsp70) family serves as molecular chaperones that play several critical roles in the cell, such as quality control of protein folding and regulation of intracellular trafficking. The versatile functions of Hsp70 rely on the allosteric interaction between its two domains: nucleotide binding domain (NBD) and substrate binding domain (SBD). They undergo very large conformational changes as the systems performs its functions, going through open/closed conformations of the SBD upon unbinding/binding of a substrate, and coupling/uncoupling of the two domains upon ATP hydrolysis.Understanding the interdomain allostery of Hsp70 is key to rational design of inhibitors, yet the mechanism of allostery remains a challenging problem. The Perturbation Response Scanning, PRS, method provides a graph theoretical approach to investigate the dynamical basis of signal transduction in proteins. This method involves the study of the response of each aminoacid to a perturbation on a given aminoacid of the system. In the present study we build upon our previous examination of the system1 and discuss the application of PRS, via elastic network models, to investigate allosteric interactions between the two domains of Hsp70. Here we analyze the covariance in the movements of different structural elements, to show how the perturbation of the interfacial interactions propagates across the two domains. The analysis sheds light on pathways that dynamically mediate the allosteric communication between the highly conserved or co-evolving sites. An all-atom molecular dynamics study shows the differences between the ATP- and ADP-bound structures of Hsp70, and provides insight into the physical forces that underlie those pathways, thus reconciling the predictions based on network connectivity considerations and the simulations performed with full atomic potentials.1Liu, Y. Gierasch, L. M. and Bahar, I. Plos Comp Biol 6:1-15 (2012)