Structural Analysis of E. coli hsp90 Reveals Dramatic Nucleotide-Dependent Conformational Rearrangements
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In eukaryotes, the ubiquitous and abundant members of the 90 kilodalton heat-shock protein (hsp90) chaperone family facilitate the folding and conformational changes of a broad array of proteins important in cell signaling, proliferation, and survival. Here we describe the effects of nucleotides on the structure of full-length HtpG, the Escherichia coli hsp90 ortholog. By electron microscopy, the nucleotide-free, AMPPNP bound, and ADP bound states of HtpG adopt completely distinct conformations. Structural characterization of nucleotide-free and ADP bound HtpG was extended to higher resolution by X-ray crystallography. In the absence of nucleotide, HtpG exhibits an "open" conformation in which the three domains of each monomer present hydrophobic elements into the large cleft formed by the dimer. By contrast, ADP binding drives dramatic conformational changes that allow these hydrophobic elements to converge and shield each other from solvent, suggesting a mechanism by which nucleotides could control client protein binding and release.
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The CSPs reflect large conformational changes of the ATP lid and proximal regions.
“As expected, chemical shift perturbations (CSPs) cluster in the NTD, which harbors the nucleotide binding site, and reflect large conformational changes of the ATP lid and proximal regions (7, 8, 10, 32, 33).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [10]
Hsp90 dimer adopts an ensemble of open conformations with a wide range of opening angles between the two protomers in both apo- and ATP-bound states.
“Our solution NMR and SAXS data show that, both in the apo- and ATP-bound states, the Hsp90 dimer adopts an ensemble of open conformations with a wide range of opening angles between the two protomers (10).”
From Client binding shifts the populations of dynamic Hsp90 conformations through an allosteric network (2021) · cites this paper as [10]
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Self-citation
- Authors
- Shiau, A. K., Harris, S. F., Southworth, D. R., & Agard, D. A.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Agard, David A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 127
- Issue
- 2
- Pages
- 329-340
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2038441129
- Cited by
- 455
- References
- 37
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 21 · 2023: 19 · 2022: 23 · 2021: 21 · 2020: 27 · 2019: 20 · 2018: 28 · 2017: 18 · 2016: 29 · 2015: 23 · 2014: 28 · 2013: 24 · 2012: 30
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Helen Hay Whitney Foundation
- University of California, San Francisco
- National Institute of Diabetes and Digestive and Kidney Diseases (P01 DK-58390, P01DK058390)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- HtpG, HSP90, ADP binding, AMP-PNP, nucleotide-free state, open conformation, hydrophobic cleft, chaperone mechanism
- MeSH terms
- Adenine Nucleotides, Adenosine Diphosphate, Adenylyl Imidodiphosphate, Binding Sites, Microscopy, Electron, Models, Molecular, Protein Binding, Protein Conformation, Protein Folding, Crystallography, X-Ray, HSP90 Heat-Shock Proteins, Dimerization, Escherichia coli Proteins
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