ATP Impedes the Inhibitory Effect of Hsp90 on Aβ40 Fibrillation

Hongzhi Wang; Max Lallemang; Bianca Hermann; Cecilia Wallin; Rolf Loch; Alain Blanc; Bizan N Balzer; Thorsten Hugel; Jinghui Luo

doi:10.1016/j.jmb.2020.11.016

ATP Impedes the Inhibitory Effect of Hsp90 on Aβ₄₀ Fibrillation

J Mol Biol. 2021 Jan 22;433(2):166717. doi: 10.1016/j.jmb.2020.11.016. Epub 2020 Nov 19.

Authors

Hongzhi Wang¹, Max Lallemang², Bianca Hermann³, Cecilia Wallin⁴, Rolf Loch¹, Alain Blanc⁵, Bizan N Balzer², Thorsten Hugel², Jinghui Luo⁶

Affiliations

¹ Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland.
² Institute of Physical Chemistry, University of Freiburg, Albertstraße 21, 79104 Freiburg, Germany; Cluster of Excellence livMatS @ FIT - Freiburg Center for Interactive Materials and Bioinspired Technologies, University of Freiburg, Georges-Köhler-Allee 105, D-79110 Freiburg, Germany.
³ Institute of Physical Chemistry, University of Freiburg, Albertstraße 21, 79104 Freiburg, Germany.
⁴ Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden.
⁵ Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, 5232 Villigen, Switzerland.
⁶ Department of Biology and Chemistry, Paul Scherrer Institute, 5232 Villigen, Switzerland. Electronic address: Jinghui.luo@psi.ch.

PMID: 33220262
DOI: 10.1016/j.jmb.2020.11.016

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone that assists protein folding in an Adenosine triphosphate (ATP)-dependent way. Hsp90 has been reported to interact with Alzheimeŕs disease associated amyloid-β (Aβ) peptides and to suppress toxic oligomer- and fibril formation. However, the mechanism remains largely unclear. Here we use a combination of atomic force microscopy (AFM) imaging, circular dichroism (CD) spectroscopy and biochemical analysis to quantify this interaction and put forward a microscopic picture including rate constants for the different transitions towards fibrillation. We show that Hsp90 binds to Aβ₄₀ monomers weakly but inhibits Aβ₄₀ from growing into fibrils at substoichiometric concentrations. ATP impedes this interaction, presumably by modulating Hsp90's conformational dynamics and reducing its hydrophobic surface. Altogether, these results might indicate alternative ways to prevent Aβ₄₀ fibrillation by manipulating chaperones that are already abundant in the brain.

Keywords: Aβ(40); Hsp90; conformation; fibrillation; hydrophobic interaction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / chemistry*
Adenosine Triphosphate / metabolism
Amyloid / chemistry*
Amyloid / metabolism
Amyloid beta-Peptides / chemistry*
Amyloid beta-Peptides / metabolism
HSP90 Heat-Shock Proteins / chemistry*
HSP90 Heat-Shock Proteins / metabolism
Hydrophobic and Hydrophilic Interactions
Microscopy, Atomic Force
Models, Molecular
Peptide Fragments / chemistry*
Peptide Fragments / metabolism
Protein Aggregates
Protein Binding
Protein Conformation
Recombinant Proteins
Spectrum Analysis
Structure-Activity Relationship

Substances

Amyloid
Amyloid beta-Peptides
HSP90 Heat-Shock Proteins
Peptide Fragments
Protein Aggregates
Recombinant Proteins
amyloid beta-protein (1-40)
Adenosine Triphosphate