The molecular chaperone, α-crystallin, inhibits amyloid formation by apolipoprotein C-II
Date
2001
Authors
Hatters, D.
Lindner, R.
Carver, J.
Howlett, G.
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Advisors
Journal Title
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Type:
Journal article
Citation
Journal of Biological Chemistry, 2001; 276(36):33755-33761
Statement of Responsibility
Danny M. Hatters, Robyn A. Lindner, John A. Carver, and Geoffrey J. Howlett
Conference Name
Abstract
Under lipid-free conditions, human apolipoprotein C-II (apoC-II) exists in an unfolded conformation that over several days forms amyloid ribbons. We examined the influence of the molecular chaperone, α-crystallin, on amyloid formation by apoC-II. Time-dependent changes in apoC-II turbidity (at 0.3 mg/ml) were suppressed potently by substoichiometric subunit concentrations of α-crystallin (1-10 μg/ml). α-Crystallin also inhibits time-dependent changes in the CD spectra, thioflavin T binding, and sedimentation coefficient of apoC-II. This contrasts with stoichiometric concentrations of α-crystallin required to suppress the amorphous aggregation of stressed proteins such as reduced α-lactalbumin. Two pieces of evidence suggest that α-crystallin directly interacts with amyloidogenic intermediates. First, sedimentation equilibrium and velocity experiments exclude high affinity interactions between α-crystallin and unstructured monomeric apoC-II. Second, the addition of α-crystallin does not lead to the accumulation of intermediate sized apoC-II species between monomer and large aggregates as indicated by gel filtration and sedimentation velocity experiments, suggesting that α-crystallin does not inhibit the relatively rapid fibril elongation upon nucleation. We propose that α-crystallin interacts stoichiometrically with partly structured amyloidogenic precursors, inhibiting amyloid formation at nucleation rather than the elongation phase. In doing so, α-crystallin forms transient complexes with apoC-II, in contrast to its chaperone behavior with stressed proteins.
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© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.