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Science 21 June 2002:
Vol. 296. no. 5576, pp. 2156 - 2157
DOI: 10.1126/science.1073844
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Perspectives

BIOCHEMISTRY:
Intramembrane Proteases--Mixing Oil and Water

Michael S. Wolfe and Dennis J. Selkoe

The report that the newly characterized signal peptide peptidase is an aspartic protease that resembles presenilin (Weihofen et al.) has generated excitement among Alzheimer's disease (AD) researchers. As Wolfe and Selkoe explain in their Perspective, the new work supplements existing evidence that presenilin (which is mutated in a rare familial form of AD) is an aspartic protease responsible for the intramembranous cleavage of many substrates, including the amyloid precursor protein.

The authors are at the Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. E-mail: mwolfe{at}rics.bwh.harvard.edu; dselkoe{at}rics.bwh.harvard.edu

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THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Active-Site Residues in the Type IV Prepilin Peptidase Homologue PibD from the Archaeon Sulfolobus solfataricus.
Z. Szabo, S.-V. Albers, and A. J. M. Driessen (2006)
J. Bacteriol. 188, 1437-1443
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The Extreme C Terminus of Presenilin 1 Is Essential for {gamma}-Secretase Complex Assembly and Activity.
A. Bergman, H. Laudon, B. Winblad, J. Lundkvist, and J. Naslund (2004)
J. Biol. Chem. 279, 45564-45572
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Functional Implications of the Presenilin Dimerization: RECONSTITUTION OF {gamma}-SECRETASE ACTIVITY BY ASSEMBLY OF A CATALYTIC SITE AT THE DIMER INTERFACE OF TWO CATALYTICALLY INACTIVE PRESENILINS.
S. Cervantes, C. A. Saura, E. Pomares, R. Gonzalez-Duarte, and G. Marfany (2004)
J. Biol. Chem. 279, 36519-36529
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Effects of RNA Interference-mediated Silencing of {gamma}-Secretase Complex Components on Cell Sensitivity to Caspase-3 Activation.
Z. Xie, D. M. Romano, D. M. Kovacs, and R. E. Tanzi (2004)
J. Biol. Chem. 279, 34130-34137
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Oma1, a Novel Membrane-bound Metallopeptidase in Mitochondria with Activities Overlapping with the m-AAA Protease.
M. Kaser, M. Kambacheld, B. Kisters-Woike, and T. Langer (2003)
J. Biol. Chem. 278, 46414-46423
   Abstract »    Full Text »    PDF »
A reporter for amyloid precursor protein {gamma}-secretase activity in Drosophila.
M. Guo, E. J. Hong, J. Fernandes, S. L. Zipursky, and B. A. Hay (2003)
Hum. Mol. Genet. 12, 2669-2678
   Abstract »    Full Text »    PDF »
Assembly of the {gamma}-Secretase Complex Involves Early Formation of an Intermediate Subcomplex of Aph-1 and Nicastrin.
M. J. LaVoie, P. C. Fraering, B. L. Ostaszewski, W. Ye, W. T. Kimberly, M. S. Wolfe, and D. J. Selkoe (2003)
J. Biol. Chem. 278, 37213-37222
   Abstract »    Full Text »    PDF »
Regulated Hyperaccumulation of Presenilin-1 and the "{gamma}-Secretase" Complex: EVIDENCE FOR DIFFERENTIAL INTRAMEMBRANOUS PROCESSING OF TRANSMEMBRANE SUBSTRATES.
S.-H. Kim, T. Ikeuchi, C. Yu, and S. S. Sisodia (2003)
J. Biol. Chem. 278, 33992-34002
   Abstract »    Full Text »    PDF »
A Region within a Lumenal Loop of Saccharomyces cerevisiae Ycf1p Directs Proteolytic Processing and Substrate Specificity.
D. L. Mason, M. P. Mallampalli, G. Huyer, and S. Michaelis (2003)
Eukaryot. Cell 2, 588-598
   Abstract »    Full Text »    PDF »
{gamma}-Secretase is a membrane protein complex comprised of presenilin, nicastrin, aph-1, and pen-2.
W. T. Kimberly, M. J. LaVoie, B. L. Ostaszewski, W. Ye, M. S. Wolfe, and D. J. Selkoe (2003)
PNAS 100, 6382-6387
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Differential Effects of Inhibitors on the gamma -Secretase Complex. MECHANISTIC IMPLICATIONS.
A. Y. Kornilova, C. Das, and M. S. Wolfe (2003)
J. Biol. Chem. 278, 16470-16473
   Abstract »    Full Text »    PDF »
Targeting Presenilin-type Aspartic Protease Signal Peptide Peptidase with gamma -Secretase Inhibitors.
A. Weihofen, M. K. Lemberg, E. Friedmann, H. Rueeger, A. Schmitz, P. Paganetti, G. Rovelli, and B. Martoglio (2003)
J. Biol. Chem. 278, 16528-16533
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Notch-induced Proteolysis and Nuclear Localization of the Delta Ligand.
C. E. Bland, P. Kimberly, and M. D. Rand (2003)
J. Biol. Chem. 278, 13607-13610
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{gamma}-Secretase--Intramembrane Protease with a Complex.
M. S. Wolfe (2003)
Sci. Aging Knowl. Environ. 2003, pe7-7
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Familial Alzheimer Disease-linked Presenilin 1 Variants Enhance Production of Both Abeta 1-40 and Abeta 1-42 Peptides That Are Only Partially Sensitive to a Potent Aspartyl Protease Transition State Inhibitor of "gamma -Secretase".
T. Ikeuchi, G. Dolios, S.-H. Kim, R. Wang, and S. S. Sisodia (2003)
J. Biol. Chem. 278, 7010-7018
   Abstract »    Full Text »    PDF »


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