Structural analyses define the molecular basis of clusterin chaperone function

Abstract

Clusterin (apolipoprotein J), a conserved glycoprotein abundant in blood and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein. Dysregulation of clusterin is linked to late-onset Alzheimer disease. Despite its prominent role in extracellular proteostasis, the mechanism of clusterin function remained unclear. Here, we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two disordered, hydrophobic peptide tails enable diverse activities. Resembling the substrate-binding regions of small heat-shock proteins, these sequences mediate clusterin’s chaperone function in suppressing amyloid-β, tau and α-synuclein aggregation. In conjunction with conserved surface areas, the tail segments also participate in clusterin binding to cell surface receptors and cellular uptake. While contributing to lipoprotein formation, the hydrophobic tails remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipids in maintaining the solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation. The authors reveal a three-domain architecture of glycoprotein clusterin and show that the hydrophobic tails are crucial for clusterin’s functions as an extracellular molecular chaperone and apolipoprotein, as well as for receptor binding and cellular uptake.