Abstract
Clusterin, a conserved secretory glycoprotein abundant in blood plasma and cerebrospinal fluid, functions as a molecular chaperone and apolipoprotein (Wyatt et al. 2013, Raulin et al. 2022). Dysregulation of clusterin is linked to late-onset Alzheimer’s disease, cardiovascular pathology and cancer (Rohne et al. 2016, Satapathy and Wilson 2021, Wilson et al. 2023). Despite its prominent role in extracellular proteostasis, the chaperone mechanism of clusterin has remained unclear. Here we present crystal structures of human clusterin, revealing a discontinuous three-domain architecture. Structure-based mutational analysis demonstrated that two intrinsically disordered, hydrophobic peptide tails enable diverse clusterin activities. Resembling the N-terminal substrate binding regions of so-called small heat shock proteins, these sequences mediate clusterin’s chaperone function in suppressing amyloid-β, tau and α-synuclein aggregation. In conjunction with highly conserved surface areas, the tail segments also participate in clusterin binding to very low density lipoprotein receptor (VLDLR) and cellular uptake. Moreover, the disordered tails cooperate with an adjacent amphipathic helix in lipoprotein formation, but remain accessible for chaperone function in the lipoprotein complex. The remarkable versatility of these sequences allows clusterin to function alone or bound to lipid in maintaining solubility of aberrant extracellular proteins and facilitating their clearance by endocytosis and lysosomal degradation.
Competing Interest Statement
The authors have declared no competing interest.
