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J. Biol. Chem., Vol. 277, Issue 42, 39062-39065, October 18, 2002
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-Secretase Complex
Required for Coordinated Expression of Presenilin and
Nicastrin*
§,,,,,,
From the The Alzheimer disease-associated presenilin (PS)
proteins apparently provide the active site of Adolf-Butenandt-Institute,
Department of Biochemistry, Laboratory for Alzheimer's and
Parkinson's Disease Research, Schillerstrasse 44, Ludwig-Maximilians-University, 80336 Munich, Germany and
¶ Boehringer Ingelheim Pharma KG, Department of CNS Research,
Birkendorferstrasse 65, 88397 Biberach/Riss, Germany
-secretase, an
unusual intramembrane-cleaving aspartyl protease. PSs principally occur
as high molecular weight protein complexes that contain nicastrin (Nct)
and additional so far unidentified components. Recently, PEN-2 has been
implicated in -secretase function. Here we identify PEN-2 as
a critical component of PS1/-secretase and PS2/-secretase
complexes. Strikingly, in the absence of PS1 and PS1/PS2, PEN-2 levels
are strongly reduced. Similarly, PEN-2 levels are reduced upon RNA
interference-mediated down-regulation of Nct. On the other side,
down-regulation of PEN-2 by RNA interference is associated with reduced
PS levels, impaired Nct maturation, and deficient -secretase complex
formation. We conclude that PEN-2 is an integral -secretase complex
component and that -secretase complex components are expressed in a
coordinated manner.
To whom correspondence may be addressed. Tel.:
49-89-5996-471/472; Fax: 49-89-5996-415; E-mail:
chaass@pbm.med.uni-muenchen.de.
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 Y. Hu and M. E. Fortini Different cofactor activities in {gamma}-secretase assembly: evidence for a nicastrin-Aph-1 subcomplex J. Cell Biol., May 26, 2003; 161(4): 685 - 690. [Abstract] [Full Text] [PDF]
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A. S. Crystal, V. A. Morais, T. C. Pierson, D. S. Pijak, D. Carlin, V. M.-Y. Lee, and R. W. Doms Membrane Topology of {gamma}-Secretase Component PEN-2 J. Biol. Chem., May 23, 2003; 278(22): 20117 - 20123. [Abstract] [Full Text] [PDF]
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A. Y. Kornilova, C. Das, and M. S. Wolfe Differential Effects of Inhibitors on the gamma -Secretase Complex. MECHANISTIC IMPLICATIONS J. Biol. Chem., May 2, 2003; 278(19): 16470 - 16473. [Abstract] [Full Text] [PDF]
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K. Shirotani, D. Edbauer, A. Capell, J. Schmitz, H. Steiner, and C. Haass gamma -Secretase Activity Is Associated with a Conformational Change of Nicastrin J. Biol. Chem., May 2, 2003; 278(19): 16474 - 16477. [Abstract] [Full Text] [PDF]
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