Binding of the Molecular Chaperone αB-crystallin to Aβ Amyloid Fibrils Inhibits Fibril Elongation

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2011 Oct 4

PMID 21961594

Citations 84

Authors

Sarah L Shammas

Christopher A Waudby

Shuyu Wang

Alexander K Buell

Tuomas P J Knowles

Heath Ecroyd

Mark E Welland

John A Carver

Christopher M Dobson

Sarah Meehan

Affiliations

Soon will be listed here.

Abstract

The molecular chaperone αB-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with Aβ amyloid fibrils in the extracellular plaques that are characteristic of Alzheimer's disease. We investigated whether this archetypical small heat-shock protein has the ability to interact with Aβ fibrils in vitro. We find that αB-crystallin binds to wild-type Aβ(42) fibrils with micromolar affinity, and also binds to fibrils formed from the E22G Arctic mutation of Aβ(42). Immunoelectron microscopy confirms that binding occurs along the entire length and ends of the fibrils. Investigations into the effect of αB-crystallin on the seeded growth of Aβ fibrils, both in solution and on the surface of a quartz crystal microbalance biosensor, reveal that the binding of αB-crystallin to seed fibrils strongly inhibits their elongation. Because the lag phase in sigmoidal fibril assembly kinetics is dominated by elongation and fragmentation rates, the chaperone mechanism identified here represents a highly effective means to inhibit fibril proliferation. Together with previous observations of αB-crystallin interaction with α-synuclein and insulin fibrils, the results suggest that this mechanism is a generic means of providing molecular chaperone protection against amyloid fibril formation.

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