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

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.