ArticleProceedings of the National Academy of Sciences of the United States of America2018
Allosteric landscapes of eukaryotic cytoplasmic Hsp70s are shaped by evolutionary tuning of key interfaces.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 46 citations in OpenAlex.
- Human Hsp70 paralogs display selective J-domain interactions tuning proteostasis under stress.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Model Peptides Enable Comparisons of Substrate Binding Modes of Hsp70 Molecular Chaperones.Biochemistry · 2026Article
- Mechanisms and regulation of the Hsp70 chaperone network.Nature reviews. Molecular cell biology · 2026Review
- Mechanisms of assembly and function of the Hsp70-Hsp40 chaperone machinery.Molecular cell · 2025Article
- Transcriptome dynamics and allele-specific regulation underlie wheat heterosis at the anthesis and grain-filling stages.BMC genomics · 2025Article
- Single-molecule study of the dynamics of the molecular chaperone Hsp70 during the functional cycle.Biochemical Society transactions · 2025Review
- Reused Protein Segments Linked to Functional Dynamics.Molecular biology and evolution · 2024Article
- Analysis of Reconstituted Tripartite Complex Supports Avidity-based Recruitment of Hsp70 by Substrate Bound J-domain Protein.Journal of molecular biology · 2023Article
- J-domain protein chaperone circuits in proteostasis and disease.Trends in cell biology · 2023Review
- Multivalent protein-protein interactions are pivotal regulators of eukaryotic Hsp70 complexes.Cell stress & chaperones · 2022Review
- Complementary protocols to evaluate inhibitors against the DnaK chaperone network.STAR protocols · 2022Article
- An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance.Cell chemical biology · 2022Article
- Allosteric Inter-Domain Contacts in Bacterial Hsp70 Are Located in Regions That Avoid Insertion and Deletion Events.International journal of molecular sciences · 2022Article
- Hsp70 in Redox Homeostasis.Cells · 2022Review
- Structural and Kinetic Views of Molecular Chaperones in Multidomain Protein Folding.International journal of molecular sciences · 2022Review
- The functions and regulation of heat shock proteins; key orchestrators of proteostasis and the heat shock response.Archives of toxicology · 2021Review
- Studying protein folding in health and disease using biophysical approaches.Emerging topics in life sciences · 2021Article
- Allosteric Mechanisms of Nonadditive Substituent Contributions to Protein-Ligand Binding.Biophysical journal · 2020Article
- Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior.Current opinion in structural biology · 2020Review
- Two-step mechanism of J-domain action in driving Hsp70 function.PLoS computational biology · 2020Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
The 70-kDa heat shock proteins (Hsp70s) are molecular chaperones that perform a wide range of critical cellular functions. They assist in the folding of newly synthesized proteins, facilitate assembly of specific protein complexes, shepherd proteins across membranes, and prevent protein misfolding and aggregation. Hsp70s perform these functions by a conserved mechanism that relies on allosteric cycles of nucleotide-modulated binding and release of client proteins. Current models for Hsp70 allostery have come from extensive study of the bacterial Hsp70, DnaK. Extending our understanding to eukaryotic Hsp70s is extremely important not only in providing a likely common mechanistic framework but also because of their central roles in cellular physiology. In this study, we examined the allosteric behaviors of the eukaryotic cytoplasmic Hsp70s, HspA1 and Hsc70, and found significant differences from that of DnaK. We found that HspA1 and Hsc70 favor a state in which the nucleotide-binding domain (NBD) and substrate-binding domain (SBD) are intimately docked significantly more as compared to DnaK. Past work established that the NBD-SBD interface and the helical lid-β-SBD interface govern the allosteric landscape of DnaK. Here, we identified sites on these interfaces that differ between eukaryotic cytoplasmic Hsp70s and DnaK. Our mutational analysis has revealed key evolutionary variations that account for the population shifts between the docked and undocked conformations. These results underline the tunability of Hsp70 functions by modulation of allosteric interfaces through evolutionary diversification and also suggest sites where the binding of small-molecule modulators could influence Hsp70 function.
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