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Cited by 18Clusterin in disease pathologyHeat shock proteins researchProtein Structure and Dynamics

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Structural analyses define the molecular basis of clusterin chaperone function

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Yuste-Checa, Patricia, Carvajal, Alonso I., Mi, Chenchen, Paatz, Sarah, Hartl, F. Ulrich, Bracher, Andreas·2025·Nature Structural & Molecular Biology
DOI 10.1038/s41594-025-01631-4PMC PMC12527946

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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.

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Metadata

Authors
Yuste-Checa, P., Carvajal, A. I., Mi, C., Paatz, S., Hartl, F. U., & Bracher, A.
Affiliations
  • Max Planck Institute of Biochemistry (DE)
  • Munich Cluster for Systems Neurology (DE)
Corresponding author
  • Hartl, F. Ulrich
  • Bracher, Andreas
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2025-08-08
Volume
32
Issue
10
Pages
2035-2045
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-025-01631-4
PMC
PMC12527946
OpenAlex
W4413055983
Cited by
18
References
7
Citations by year
2026: 18
FWCI
7.45
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
Funders
  • Max-Planck-Förderstiftung
  • Deutsche Forschungsgemeinschaft (EXC 2145, EXC 2145SyNergy, 390857198)
  • European Synchrotron Radiation Facility (ID23‐1)
  • Max-Planck-Gesellschaft
  • Max-Planck-Institut für Bildungsforschung
Topics
  • Health Sciences › Medicine › Oncology › Clusterin in disease pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
clusterin, molecular chaperones, protein aggregation inhibition, amyloid-beta, tau protein, alpha-synuclein, intrinsically disordered regions, crystal structure, Alzheimer's disease, endocytosis, lysosomal degradation, cell surface receptor binding
MeSH terms
Protein Domains, Amino Acid Sequence, Humans, Models, Molecular, Protein Binding, Amyloid beta-Peptides, Crystallography, X-Ray, Molecular Chaperones, Clusterin, alpha-Synuclein

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