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Toward understanding allosteric signaling mechanisms in the ATPase domain of molecular chaperones.

ABSTRACT: The ATPase cycle of the heat shock protein 70 (HSP70) is largely dependent on the ability of its nucleotide binding domain (NBD), also called ATPase domain, to undergo structural changes between its open and closed conformations. We present here a combined study of the Hsp70 NBD sequence, structure and dynamic features to identify the residues that play a crucial role in mediating the allosteric signaling properties of the ATPase domain. Specifically, we identify the residues involved in the shortest-path communications of the domain modeled as a network of nodes (residues) and links (equilibrium interactions). By comparing the calculations on both closed and open conformation of Hsp70 NBD, we identified a subset of central residues located at the interface between the two lobes of the NBD near the nucleotide binding site, which form a putative communication pathway invariant to structural changes. Two pairs of residues forming contacts at the interface in the closed conformation of the NBD are observed to no longer interact in the open conformation, suggesting that these specific interactions may play a switch role in establishing the transition of the NBD between the two functional forms. Sequence co-evolution analysis and collective dynamics analysis with elastic network model further confirm the key roles of these residues in Hsp70 NBD dynamics and functions.

SUBMITTER: Liu Y

PROVIDER: S-EPMC2938181 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Toward understanding allosteric signaling mechanisms in the ATPase domain of molecular chaperones.

Liu Ying Y Bahar Ivet I

Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing 20100101

The ATPase cycle of the heat shock protein 70 (HSP70) is largely dependent on the ability of its nucleotide binding domain (NBD), also called ATPase domain, to undergo structural changes between its open and closed conformations. We present here a combined study of the Hsp70 NBD sequence, structure and dynamic features to identify the residues that play a crucial role in mediating the allosteric signaling properties of the ATPase domain. Specifically, we identify the residues involved in the sho ...[more]

PMID: 19908379

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Project description:The versatile functions of the heat shock protein 70 (Hsp70) family of molecular chaperones rely on allosteric interactions between their nucleotide-binding and substrate-binding domains, NBD and SBD. Understanding the mechanism of interdomain allostery is essential to rational design of Hsp70 modulators. Yet, despite significant progress in recent years, how the two Hsp70 domains regulate each other's activity remains elusive. Covariance data from experiments and computations emerged in recent years as valuable sources of information towards gaining insights into the molecular events that mediate allostery. In the present study, conservation and covariance properties derived from both sequence and structural dynamics data are integrated with results from Perturbation Response Scanning and in vivo functional assays, so as to establish the dynamical basis of interdomain signal transduction in Hsp70s. Our study highlights the critical roles of SBD residues D481 and T417 in mediating the coupled motions of the two domains, as well as that of G506 in enabling the movements of the ?-helical lid with respect to the ?-sandwich. It also draws attention to the distinctive role of the NBD subdomains: Subdomain IA acts as a key mediator of signal transduction between the ATP- and substrate-binding sites, this function being achieved by a cascade of interactions predominantly involving conserved residues such as V139, D148, R167 and K155. Subdomain IIA, on the other hand, is distinguished by strong coevolutionary signals (with the SBD) exhibited by a series of residues (D211, E217, L219, T383) implicated in DnaJ recognition. The occurrence of coevolving residues at the DnaJ recognition region parallels the behavior recently observed at the nucleotide-exchange-factor recognition region of subdomain IIB. These findings suggest that Hsp70 tends to adapt to co-chaperone recognition and activity via coevolving residues, whereas interdomain allostery, critical to chaperoning, is robustly enabled by conserved interactions.

Dataset Information

Toward understanding allosteric signaling mechanisms in the ATPase domain of molecular chaperones.

Publications

Toward understanding allosteric signaling mechanisms in the ATPase domain of molecular chaperones.

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