Binding of the molecular chaperone ?B-crystallin to A? amyloid fibrils inhibits fibril elongation.

ABSTRACT: The molecular chaperone ?B-crystallin is a small heat-shock protein that is upregulated in response to a multitude of stress stimuli, and is found colocalized with A? 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 A? fibrils in vitro. We find that ?B-crystallin binds to wild-type A?(42) fibrils with micromolar affinity, and also binds to fibrils formed from the E22G Arctic mutation of A?(42). Immunoelectron microscopy confirms that binding occurs along the entire length and ends of the fibrils. Investigations into the effect of ?B-crystallin on the seeded growth of A? fibrils, both in solution and on the surface of a quartz crystal microbalance biosensor, reveal that the binding of ?B-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 ?B-crystallin interaction with ?-synuclein and insulin fibrils, the results suggest that this mechanism is a generic means of providing molecular chaperone protection against amyloid fibril formation.

SUBMITTER: Shammas SL 

PROVIDER: S-EPMC3183811 | biostudies-other | 2011 Oct

REPOSITORIES: biostudies-other