Mechanisms of divalent cation associated amyloidosis

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): The conversion of normally soluble proteins into amyloid fibers has pathological and functional consequences in a number of human diseases. A general cause for amyloid formation is not known. However, in many types of fiber formation, interaction of the protein precursors with divalent metals promotes aggregation. Divalent metals, particularly Cu2+, have been implicated as a central component in the formation of amyloid fibers in an increasing number of diseases. These include amyloid-beta in Alzheimer's, prion protein in Creutzfeldt-Jakob Disease, immunoglobulin light chain in Light Chain Amyloidosis, alpha-synuclein in Parkinson's, and beta-2-microglobulin (beta2m) in Dialysis Related Amyloidosis (DRA). Interaction with divalent metals may act to induce novel structure, preferentially bind amyloidogenic intermediates, or catalyze the sampling of a refolding pathway which contains amyloidogenic intermediates. The experiments proposed here will investigate the molecular basis for divalent metal associated amyloid formation in DRA. The first aim of this work is to determine the kinetics and pathway of Cu2+ associated fibrillogenesis of beta2m. The second aim is to determine the structure of a well-defined amyloidogenic precursor formed in the presence of Cu2+. The third aim is to determine the unfolded state structure of beta2m formed in the presence of divalent metal. These experiments will aid in understanding amyloid formation in DRA, but also contribute to establishing a general model for divalent metal associated amyloid formation.