Abstract
The stress-induced 70 kDa heat shock protein (Hsp70) functions as a molecular chaperone to maintain protein homeostasis. Hsp70 contains an N-terminal ATPase domain (NBD) and a C-terminal substrate-binding domain (SBD). The SBD is divided into the β subdomain containing the substrate-binding site (βSBD) and the α-helical subdomain (αLid) that covers the βSBD. In this report, the solution structures of two different forms of the SBD from human Hsp70 were solved. One structure shows the αLid bound to the substrate-binding site intramolecularly, whereas this intramolecular binding mode is absent in the other structure solved. Structural comparison of the two SBDs from Hsp70 revealed that client-peptide binding rearranges residues at the interdomain contact site, which impairs interdomain contact between the SBD and the NBD. Peptide binding also disrupted the inter-subdomain interaction connecting the αLid to the βSBD, which allows the binding of the αLid to the NBD. The results provide a mechanism for interdomain communication upon substrate binding from the SBD to the NBD via the lynchpin site in the βSBD of human Hsp70. In comparison to the bacterial ortholog, DnaK, some remarkable differences in the allosteric signal propagation among residues within the Hsp70 SBD exist.
Highlights
Heat shock protein 70 (Hsp70) molecular chaperones engage in a wide range of cellular processes integral to protein homeostasis [1,2]
We found that substrate binding to β subdomain containing the substrate-binding site (βSBD) causes an allosteric change to disrupt the α-helical subdomain (αLid)-βSBD interaction to give rise to αLid conformational dynamics, which facilitates αLid contact with NBD to occur in the ATP-bound form of Hsp70
By solving the solution structures of substrate-binding domain (SBD)(∆CDE) and SBD(∆CDE)-y we have revealed two aspects of the response of Hsp70-SBD upon binding to a client-peptide
Summary
Heat shock protein 70 (Hsp70) molecular chaperones engage in a wide range of cellular processes integral to protein homeostasis [1,2]. These ATP-dependent chaperones monitor various protein-folding processes in cells through their promiscuous binding to proteins in unfolded, misfolded, or aggregated states but not to their folded counterparts [3,4]. Some Hsp members are expressed constitutively, whereas others are stress-induced [5]. The stress-inducible human Hsp ( called HSPA1A) is of particular interest because of its potential role in keeping cancer cells alive by preventing the formation of toxic protein aggregates that frequently occur in Molecules 2018, 23, 528; doi:10.3390/molecules23030528 www.mdpi.com/journal/molecules
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