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Originally published In Press as doi:10.1074/jbc.M105285200 on July 10, 2001

J. Biol. Chem., Vol. 276, Issue 36, 33755-33761, September 7, 2001
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The Molecular Chaperone, alpha -Crystallin, Inhibits Amyloid Formation by Apolipoprotein C-II*

Danny M. HattersDagger §, Robyn A. Lindner, John A. Carver, and Geoffrey J. HowlettDagger ||

From the Dagger  Department of Biochemistry and Molecular Biology, the University of Melbourne, Parkville, Victoria 3010 and the  Department of Chemistry, University of Wollongong, Northfields Avenue, Wollongong, New South Wales 2522, Australia

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, alpha -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 alpha -crystallin (1-10 µg/ml). alpha -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 alpha -crystallin required to suppress the amorphous aggregation of stressed proteins such as reduced alpha -lactalbumin. Two pieces of evidence suggest that alpha -crystallin directly interacts with amyloidogenic intermediates. First, sedimentation equilibrium and velocity experiments exclude high affinity interactions between alpha -crystallin and unstructured monomeric apoC-II. Second, the addition of alpha -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 alpha -crystallin does not inhibit the relatively rapid fibril elongation upon nucleation. We propose that alpha -crystallin interacts stoichiometrically with partly structured amyloidogenic precursors, inhibiting amyloid formation at nucleation rather than the elongation phase. In doing so, alpha -crystallin forms transient complexes with apoC-II, in contrast to its chaperone behavior with stressed proteins.

* This work was supported in part by grants from the National Health and Medical Research Council of Australia (to G. J. H. and J. A. C.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of a Melbourne Research Postgraduate Scholarship.

|| To whom correspondence should be addressed. Tel.: 61 3 8344 7632; Fax: 61 3 9347 7730; E-mail ghowlett@unimelb.edu.au.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.