Allostery in Hsp70 Chaperones Is Transduced by Subdomain Rotations

Akash Bhattacharya, Alexander V. Kurochkin, Grover N.B. Yip, Yongbo Zhang, Eric B. Bertelsen, Erik R.P. Zuiderweg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


Hsp70s (heat shock protein 70 kDa) are central to protein folding, refolding, and trafficking in organisms ranging from archaea to Homo sapiens under both normal and stressed cellular conditions. Hsp70s are comprised of a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The nucleotide binding site in the NBD and the substrate binding site in the SBD are allosterically linked: ADP binding promotes substrate binding, while ATP binding promotes substrate release. Hsp70s have been linked to inhibition of apoptosis (i.e., cancer) and diseases associated with protein misfolding such as Alzheimer's, Parkinson's, and Huntington's. It has long been a goal to characterize the nature of allosteric coupling in these proteins. However, earlier studies of the isolated NBD could not show any difference in overall conformation between the ATP state and the ADP state. Hence the question: How is the state of the nucleotide communicated between NBD and SBD? Here we report a solution NMR study of the 44-kDa NBD of Hsp70 from Thermus thermophilus in the ADP and AMPPNP states. Using the solution NMR methods of residual dipolar coupling analysis, we determine that significant rotations occur for different subdomains of the NBD upon exchange of nucleotide. These rotations modulate access to the nucleotide binding cleft in the absence of a nucleotide exchange factor. Moreover, the rotations cause a change in the accessibility of a hydrophobic surface cleft remote from the nucleotide binding site, which previously has been identified as essential to allosteric communication between NBD and SBD. We propose that it is this change in the NBD surface cleft that constitutes the allosteric signal that can be recognized by the SBD.

Original languageEnglish (US)
Pages (from-to)475-490
Number of pages16
JournalJournal of Molecular Biology
Issue number3
StatePublished - May 8 2009


  • allostery
  • dnak
  • dynamics
  • nmr
  • structure

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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