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J. Biol. Chem., Vol. 278, Issue 36, 34259-34267, September 5, 2003

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Folding and Stability of the Extracellular Domain of the Human Amyloid Precursor Protein^*

Michelle G. Botelho , Matthias Gralle , Cristiano L. P. Oliveira  ¶, Iris Torriani  ¶ and Sérgio T. Ferreira  ¶ ||

From the Department of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21944-590, Brazil, Instituto de Física "Gleb Wataghin," Unicamp, Campinas, SP 13084-971, Brazil, and ^¶Laboratório Nacional de Luz Síncrotron, Campinas, SP 13084-9701, Brazil

The -amyloid peptide (A), the major component of the senile plaques found in the brains of Alzheimer's disease patients, is derived from proteolytic processing of a transmembrane glycoprotein known as the amyloid precursor protein (APP). Human APP exists in various isoforms, of which the major ones contain 695, 751, and 770 amino acids. Proteolytic cleavage of APP by - or -secretases releases the extracellular soluble fragments sAPP or sAPP, respectively. Despite the fact that sAPP plays important roles in both physiological and pathological processes in the brain, very little is known about its structure and stability. We have recently presented a structural model of sAPP₆₉₅ obtained from small-angle x-ray scattering measurements (Gralle, M., Botelho, M. M., Oliveira, C. L. P., Torriani, I., and Ferreira, S. T. (2002) Biophys. J. 83, 3513–3524). We now report studies on the folding and stabilities of sAPP₆₉₅ and sAPP₇₇₀. The combined use of intrinsic fluorescence, 4–4'-Dianilino-1,1'binaphthyl-5,5'-disulfonic acid (bis-ANS) fluorescence, circular dichroism, differential ultraviolet absorption, and small-angle x-ray scattering measurements of the equilibrium unfolding of sAPP₆₉₅ and sAPP₇₇₀ by GdnHCl and urea revealed multistep folding pathways for both sAPP isoforms. Such stepwise folding processes may be related to the identification of distinct structural domains in the three-dimensional model of sAPP. Furthermore, the relatively low stability of the native state of sAPP suggests that conformational plasticity may play a role in allowing APP to interact with a number of distinct physiological ligands.

Received for publication, March 27, 2003 , and in revised form, June 2, 2003.

^* This work was supported by grants from the John Simon Guggenheim Memorial Foundation, Howard Hughes Medical Institute, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro, and Financiadora de Estudos e Projetos (to S. T. F.) and by Fundação de Amparo à Pesquisa do Estado de São Paulo and Laboratório Nacional de Luz Síncrotron. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| A Howard Hughes Medical Institute International Scholar. To whom correspondence should be addressed. Tel./Fax: 5521-2562-6789; E-mail: ferreira{at}bioqmed.ufrj.br.

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