Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations

Federica Chiappori,Giorgio Colombo,Ivan Merelli,Giulia Morra,Luciano Milanesi,Qiang Cui

doi:10.1371/journal.pcbi.1002844

Abstract

Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.

Highlights

Heat shock proteins (HSPs) are essential macromolecules involved in housekeeping cellular activities, whose expression levels can be modulated in response to environmental conditions
A comparative analysis of both Hsp70 and its non-allosteric homolog Hsp110 is carried out in order to identify the determinants of the allosteric mechanisms at the atomic level
The functional cycle of the protein entails a transition from the closed state in the presence of ADP (Figure 1B), represented by the crystal structure of ADP-bound DnaK [9], to the open state in the presence of ATP, represented by the ATP-bound conformation of yeast Sse1 [12]

Summary

Introduction

Heat shock proteins (HSPs) are essential macromolecules involved in housekeeping cellular activities, whose expression levels can be modulated in response to environmental conditions. Given its involvement in many cellular control and regulation processes, recent studies have shown a key role of Hsp in several diseases: some of these, for instance several cancer types (breast, endometrial, oral, colorectal, prostate cancers, and certain leukemias) are associated with overactivity/overexpression of the chaperone [5]. Defects in Hsp70’s activity and consequent abnormal protein misfolding and accumulation are involved in neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington [5], and in aging processes [6], [7]. This evidence points to Hsp as an interesting drug target [5], [7], [8]

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