ATP Impedes the Inhibitory Effect of Hsp90 on Aβ(40) Fibrillation

• 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 Alzheimer's disease associated amyloid-beta (A beta) 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 A beta(40) monomers weakly but inhibits A beta(40) 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 A beta(40) fibrillation by manipulating chaperones that are already abundant in the brain.

Subject headings

NATURVETENSKAP  -- Biologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences (hsv//eng)

Keyword

Hsp90

Aβ(40)

fibrillation

conformation

hydrophobic interaction

Publication and Content Type

ref (subject category)

art (subject category)