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Related Experiment Video

Updated: Jun 5, 2025

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay
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Design principles to tailor Hsp104 therapeutics.

JiaBei Lin1, Peter J Carman2, Craig W Gambogi2

  • 1Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Cell Reports
|December 13, 2024
PubMed
Summary

Hsp104 protein disaggregase activity is regulated by ATP/ADP binding. Rational design of Hsp104-Hsp70 interactions offers therapeutic potential for proteinopathies.

Keywords:
ALS/FTDCP: Molecular biologyFUSHsp104Hsp70TDP-43disaggregaseneurodegenerationprotein engineering

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Area of Science:

  • Molecular Biology
  • Protein Biochemistry
  • Biophysics

Background:

  • The hexameric AAA+ disaggregase Hsp104 solubilizes aggregated proteins by collaborating with Hsp70 and Hsp40 chaperones.
  • The precise mechanisms by which ATP- or ADP-bound states of Hsp104's middle domain (MD) regulate its hexameric function and chaperone interactions are not fully understood.

Purpose of the Study:

  • To elucidate the structural basis of Hsp104 regulation by ATP/ADP-specific middle domain configurations.
  • To investigate how these configurations modulate interactions with Hsp70 and Hsp40.
  • To establish design principles for tailoring Hsp104 activity for therapeutic applications.

Main Methods:

  • Biochemical assays to assess Hsp104 disaggregase activity and chaperone interactions.
  • Structural analysis to define nucleotide-specific protein-protein contact networks.
  • Site-directed mutagenesis and rational design to manipulate Hsp104-Hsp70 collaboration.
  • Cell-based assays to evaluate the efficacy of engineered Hsp104 variants in counteracting proteinopathies.

Main Results:

  • An ATP-specific interprotomer contact network between NBD1 and MD helix L1 was identified, tuning Hsp70 collaboration.
  • Perturbing this network yielded variants with altered Hsp70/Hsp40 collaboration, including Hsp70-independent and class B Hsp40-selective forms.
  • ADP-specific intraprotomer contacts between MD helix L2 and NBD1 restrict activity; their disruption potentiates Hsp104.
  • Rational design of the NBD1:MD helix L1 interface allowed fine-tuned Hsp70 collaboration, leading to potentiated Hsp104 activity with minimized toxicity.

Conclusions:

  • Structural insights reveal how ATP/ADP states dictate Hsp104 hexamer dynamics and chaperone interactions.
  • Targeted modulation of the NBD1:MD helix L1 interface provides a strategy for safe Hsp104 potentiation.
  • Engineered Hsp104 variants show promise for treating FUS and TDP-43 proteinopathies, establishing design principles for Hsp104-based therapeutics.