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Originally published In Press as doi:10.1074/jbc.M204801200 on November 5, 2002

J. Biol. Chem., Vol. 278, Issue 4, 2444-2451, January 24, 2003
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Conformational Switching and Fibrillogenesis in the Amyloidogenic Fragment of Apolipoprotein A-I*

Alessia AndreolaDagger §, Vittorio BellottiDagger §||, Sofia GiorgettiDagger , Palma MangioneDagger , Laura Obici§, Monica StoppiniDagger , Jaume Torres**Dagger Dagger , Enrico Monzani§§, Giampaolo MerliniDagger §, and Margaret Sunde**¶¶

From the Dagger  Department of Biochemistry and  Centro Interdipartimentale di Biologia Applicata, University of Pavia, Via Taramelli 3b, §§ Department of Chemistry, University of Pavia, Via Taramelli 12, and § Biotechnology Laboratories Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, P. le Golgi 2, 27100 Pavia, Italy and ** Department of Biochemistry, University of Cambridge, Tennis Court Rd. 80, Cambridge CB2 1GA, United Kingdom

The N-terminal portion of apolipoprotein A-I corresponding to the first 93 residues has been identified as the main component of apolipoprotein A-I fibrils in a form of systemic amyloidosis. We have been able to characterize the process of conformational switching and fibrillogenesis in this fragment of apolipoprotein A-I purified directly from ex vivo amyloid material. The peptide exists in an unstructured form in aqueous solution at neutral pH. The acidification of the solution provokes a collapse into a more compact, intermediate state and the transient appearance of a helical conformation that rapidly converts to a stable, mainly beta -structure in the fibrils. The transition from helical to sheet structure occurs concomitantly with peptide self-aggregation, and fibrils are detected after 72 h. The alpha -helical conformation is induced by the addition of trifluoroethanol and phospholipids. Interaction of the amyloidogenic polypeptide with phospholipids prevents the switching from helical to beta -sheet form and inhibits fibril formation. The secondary structure propensity of the apolipoprotein A-I fragment appears poised between helix and the beta -sheet. These findings reinforce the idea of a delicate balance between natively stabilizing interactions and fatally stabilizing interactions and stress the importance of cellular localization and environment in the maintenance of protein conformation.

* The work was supported by funds from the Ministero della Sanità (ricerca finalizzata sulla Malattia di Alzheimer code 020ALZ00/01), the MURST (Cofin 2000 protocol MM05221899), FIRB 2002 protocol RBNE01S29H, and Fondazione Telethon-Italia Grant 164-11477.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.

|| To whom correspondence should be addressed. Tel.: 39-0382-507783; Fax: 39-0382-423108; E-mail: vbellot@unipv.it.

Dagger Dagger Current address: School of Biological Sciences, Nanyang Technological University, 637616 Singapore.

¶¶ Current address: School of Molecular and Microbial Biosciences, University of Sydney, NSW 2006, Australia.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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