Journal of Biological Chemistry
Volume 272, Issue 39, 26 September 1997, Pages 24536-24541
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CELL BIOLOGY AND METABOLISM
Endoproteolytic Processing and Stabilization of Wild-type and Mutant Presenilin*

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Presenilin 1 (PS1), mutated in pedigrees of early-onset familial Alzheimer's disease, is a polytopic integral membrane protein that is endoproteolytically cleaved into 27-kDa N-terminal and 17-kDa C-terminal fragments. Although these fragments are the principal PS1 species found in normal mammalian brain, the role of endoproteolysis in the maturation of PS1 has been unclear. The present study, which uses stably transfected mouse neuroblastoma N2a cells, demonstrates that full-length polypeptides, derived from either wild-type or A246E FAD-mutant human (hu) PS1, are relatively short-lived (t½ 1.5 h) proteins that give rise to the N- and C-terminal PS1 fragments, which are more stable (t½ ∼ 24 h). N-terminal fragments, generated artificially by engineering a stop codon at amino acid 306 (PS1–306) of wild-type huPS1, were short-lived, whereas an FAD-linked variant that lacked exon 9 (ΔE9) and was not endoproteolytically cleaved exhibited a long half-life. These observations suggest that endoproteolytic cleavage and stability are not linked, leading us to propose a model in which wild-type full-length huPS1 molecules are first stabilized then subsequently endoproteolytically cleaved to generate the N- and C-terminal fragments. These fragments appear to represent the mature and functional forms of wild-type huPS1.

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*

This work was supported by the United States Public Health Service, National Institutes of Health Grants NS10580, AG07914, AG05146, NS 20471, and AG14248, the Alzheimer's Association (to D. R. B. and S. S. S.), the Develbiss Fund, and the Adler Foundation.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.