The Presenilin 1 Protein Is a Component of a High Molecular Weight Intracellular Complex That Contains β-Catenin*
- Gang Yu‡,
- Fusheng Chen‡,
- Georges Levesque‡,
- Masaki Nishimura‡,
- Dong-Mei Zhang‡,
- Lyne Levesque‡,
- Ekatarina Rogaeva‡,
- Donghong Xu‡,
- Yan Liang‡,
- Monika Duthie‡,
- Peter H. St George-Hyslopद and
- Paul E. Fraser‡
- From the ‡Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, Ontario M5S 3H2, Canada and §Department of Medicine (Division of Neurology), the Toronto Hospital, Toronto, Ontario M5S 3H2, Canada
Abstract
The presenilin (PS) genes associated with Alzheimer disease encode polytopic transmembrane proteins which undergo physiologic endoproteolytic cleavage to generate stable NH2- and COOH-terminal fragments (NTF or CTF) which co-localize in intracellular membranes, but are tightly regulated in their stoichiometry and abundance. We have used linear glycerol velocity and discontinuous sucrose gradient analysis to investigate the distribution and native conformation of PS1 and PS2 during this regulated processing in cultured cells and in brain. The PS1 NTF and CTF co-localize in the endoplasmic reticulum (ER) and in the Golgi apparatus, where they are components of a ∼250-kDa complex. This complex also contains β-catenin but not β-amyloid precursor protein (APP). In contrast, the PS1 holoprotein precursor is predominantly localized to the rough ER and smooth ER, where it is a component of a ∼180-kDa native complex. PS2 forms similar but independent complexes. Restricted incorporation of the presenilin NTF and CTF along with a potentially functional ligand (β-catenin) into a multimeric complex in the ER and Golgi apparatus may provide an explanation for the regulated accumulation of the NTF and CTF.
Footnotes
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↵* This work was supported by grants from the Medical Research Council of Canada, Alzheimer Association of Ontario, EJLB Foundation, Howard Hughes Medical Research Foundation, Scottish Rite Charitable Foundation, the Helen B. Hunter Fellowship (to G. Y.), the Alzheimer Society of Canada Fellowship (to G. L.), and the Peterborough-Burgess Fellowship (to E. R.).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.
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↵¶ To whom correspondence should be addressed: Centre for Research in Neurodegenerative Disease, Tanz Neuroscience Bldg., University of Toronto, 6, Queen’s Park Crescent, Toronto, Ontario M5S 3H2, Canada. Tel.: 416-978-7461; Fax: 416-978-1878; E-mail:p.hyslop{at}utoronto.ca.
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↵1 The abbreviations used are: PS, presenilin; TM, transmembrane; APP, amyloid precursor protein; CTF, COOH-terminal fragment; NTF, NH2-terminal fragment; ER, endoplasmic reticulum, sER and rER, smooth and rough endoplasmic reticulum.
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↵2 G. Levesque, G. Yu, M. Nishimura, D. M. Zhang, D. Xu, Y. Liang, E. Rogaeva, M. Ikeda, M. Duthie, L. Levesque, N. Murgolo, L. Wang, P. VanderVere, M. L. Bayne, C. D. Strader, J. M. Rommens, P. E. Fraser, P. St George-Hyslop, manuscript submitted for publication.
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- Received February 4, 1998.
- Revision received April 6, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
