| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 275, Issue 52, 40925-40932, December 29, 2000
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the The familial Alzheimer's disease-associated
presenilins (PSs) occur as a dimeric complex of proteolytically
generated fragments, which functionally supports endoproteolysis of
Notch and the
A Loss of Function Mutant of the Presenilin Homologue SEL-12
Undergoes Aberrant Endoproteolysis in Caenorhabditis
elegans and Increases A
42 Generation in Human Cells*
,
,,,, and**
Adolf Butenandt-Institute, Department of Biochemistry,
Laboratory for Alzheimer's Disease Research,
Ludwig-Maximilians-University, 80336 Munich, Germany, the § Genzentrum,
Ludwig-Maximilians-University, 81377 Munich, Germany, and the
Boehringer Ingelheim KG, CNS Research, 55216 Ingelheim,
Germany
-amyloid precursor protein (APP). A homologous
gene, sel-12, has been identified in Caenorhabditis
elegans. We now demonstrate that wild-type (wt) SEL-12 undergoes
endoproteolytic cleavage in C. elegans similar to the PSs
in human tissue. In contrast, SEL-12 C60S protein expressed from the
sel-12(ar131) allele is miscleaved in C. elegans, resulting in a larger mutant N-terminal fragment. Neither SEL-12 wt nor C60S undergo endoproteolytic processing upon
expression in human cells, suggesting that SEL-12 is cleaved by a
C. elegans-specific endoproteolytic activity. The loss of function of sel-12 in C. elegans is not
associated with a dominant negative activity in human cells, because
SEL-12 C60S and the corresponding PS1 C92S mutation do not interfere
with Notch1 cleavage. Moreover, both mutant variants increase the
aberrant production of the highly amyloidogenic 42-amino acid version
of amyloid -peptide similar to familial Alzheimer's
disease-associated human PS mutants. Our data therefore demonstrate
that the C60S mutation in SEL-12 is associated with aberrant
endoproteolysis and a loss of function in C. elegans,
whereas a gain of misfunction is observed upon expression in human cells.
*
This work was supported by grants from the European
Community (to C. H.) and from the Deutsche Forschungsgemeinschaft (to R. B.).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.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Okamoto, Y. Mori, Y. Komoda, T. Okamoto, M. Okochi, M. Takeda, T. Suzuki, K. Moriishi, and Y. Matsuura Intramembrane Processing by Signal Peptide Peptidase Regulates the Membrane Localization of Hepatitis C Virus Core Protein and Viral Propagation J. Virol., September 1, 2008; 82(17): 8349 - 8361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tagami, M. Okochi, K. Yanagida, A. Ikuta, A. Fukumori, N. Matsumoto, Y. Ishizuka-Katsura, T. Nakayama, N. Itoh, J. Jiang, et al. Regulation of Notch Signaling by Dynamic Changes in the Precision of S3 Cleavage of Notch-1 Mol. Cell. Biol., January 1, 2008; 28(1): 165 - 176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Ren, D. Schenk, G. S. Basi, and I. P. Shapiro Amyloid -Protein Precursor Juxtamembrane Domain Regulates Specificity of {gamma}-Secretase-dependent Cleavages J. Biol. Chem., November 30, 2007; 282(48): 35350 - 35360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Okochi, A. Fukumori, J. Jiang, N. Itoh, R. Kimura, H. Steiner, C. Haass, S. Tagami, and M. Takeda Secretion of the Notch-1 Abeta-like Peptide during Notch Signaling J. Biol. Chem., March 24, 2006; 281(12): 7890 - 7898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Wines-Samuelson and J. Shen Presenilins in the Developing, Adult, and Aging Cerebral Cortex Neuroscientist, October 1, 2005; 11(5): 441 - 451. [Abstract] [PDF]
|
|
|
|
 |
|
 A. P. Grigorenko, Y. K. Moliaka, M. C. Soto, C. C. Mello, and E. I. Rogaev The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins PNAS, October 12, 2004; 101(41): 14955 - 14960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Ellerbrock, E. M. Coscarelli, M. E. Gurney, and T. G. Geary Screening for Presenilin Inhibitors Using the Free-Living Nematode, Caenorhabditis elegans J Biomol Screen, March 1, 2004; 9(2): 147 - 152. [Abstract] [PDF]
|
|
|
|
|
|
N. Takasugi, Y. Takahashi, Y. Morohashi, T. Tomita, and T. Iwatsubo The Mechanism of gamma -Secretase Activities through High Molecular Weight Complex Formation of Presenilins Is Conserved in Drosophila melanogaster and Mammals J. Biol. Chem., December 13, 2002; 277(51): 50198 - 50205. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Chen, Y. Gu, H. Hasegawa, X. Ruan, S. Arawaka, P. Fraser, D. Westaway, H. Mount, and P. St George-Hyslop Presenilin 1 Mutations Activate gamma 42-Secretase but Reciprocally Inhibit epsilon -Secretase Cleavage of Amyloid Precursor Protein (APP) and S3-Cleavage of Notch J. Biol. Chem., September 20, 2002; 277(39): 36521 - 36526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tomita, T. Watabiki, R. Takikawa, Y. Morohashi, N. Takasugi, R. Kopan, B. De Strooper, and T. Iwatsubo The First Proline of PALP Motif at the C Terminus of Presenilins Is Obligatory for Stabilization, Complex Formation, and gamma -Secretase Activities of Presenilins J. Biol. Chem., August 24, 2001; 276(35): 33273 - 33281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Wolfe and C. Haass The Role of Presenilins in gamma -Secretase Activity J. Biol. Chem., February 16, 2001; 276(8): 5413 - 5416. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |
