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.
Highlights
Heat shock protein 90 (Hsp90) is a ubiquitously expressed, evolutionarily conserved, and highly dynamic molecular chaperone, which mainly consists of three structural domains: an N-terminal Adenosine triphosphate (ATP)-binding domain, a middle domain for client protein binding, and a C-terminal dimerization domain.[1]
The larger Ab40 aggregates observed in the presence of the Hsp[90] tetramer may result from the coaggregation with the Ab40 peptides and the aggregation-prone tetramer. This result indicates interfere with Ab fibrillation in an ATP-dependent and/or specific way? How do different Hsp[90] conformations influence Ab fibrillation? In which phase that Hsp[90] proteins suppress the formation of
Based on our atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy results, we suggest that Hsp[90] structurally modulates the transition pathway of Ab40 aggregation and morphologically impedes the formation of Ab40 fibrils
Summary
Heat shock protein 90 (Hsp90) is a ubiquitously expressed, evolutionarily conserved, and highly dynamic molecular chaperone, which mainly consists of three structural domains: an N-terminal ATP-binding domain, a middle domain for client protein binding, and a C-terminal dimerization domain.[1]. It participates in a variety of cellular processes including cell survival, hormone signaling, cell cycle control and response to cellular (heat) stress,[5,6,7,8,9] as well as in assisting folding, maturation and degradation of more than 200 ‘client proteins’ in eukaryotes.[10,11,12,13] These functions of Hsp[90] are achieved in concert with different co-chaperones and adaptor proteins and often with the help of ATP.[8,14]
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