| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 279, Issue 40, 41340-41345, October 1, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
-Secretase Complexes with Different APH-1 Variants*
From the Adolf-Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Schillerstrasse 44, Ludwig-Maximilians-University, 80336 Munich, Germany
The 
-secretase complex catalyzes the final intramembraneous cleavage of the 
-amyloid precursor protein, liberating the neurotoxic amyloid -peptide implicated in Alzheimer's disease. Apart from the catalytic subunit presenilin (PS), three additional subunits, nicastrin, APH-1, and PEN-2, have been identified. In mammals, two PS homologues, PS1 and PS2, which are part of distinct -secretase complexes, exist. Likewise, two APH-1 homologues, APH-1a and APH-1b, have been identified. Furthermore, two APH-1a splice forms, APH-1aS and APH-1aL, have been reported. Here we show that both APH-1a splice forms and APH-1b are expressed in peripheral and neuronal cells. APH-1aS, APH-1aL, and APH-1b form separate, proteolytically active -secretase complexes containing either one of the two PSs. Deficiency of APH-1a caused a decrease in nicastrin, PS, and PEN-2 levels and an increase in the levels of APH-1b, whereas deficiency of APH-1b did not affect the levels of APH-1a or the other complex components. Consistent with this finding, we found that deficiency of APH-1a was associated with reduced -secretase activity, whereas deficiency of APH-1b was not. Thus, APH-1b -secretase complexes may fulfill redundant functions. Taken together, our results suggest that, dependent on the tissue expression of the individual subunits, six distinct -secretase complexes composed of the known subunits can exist in human cells.
Received for publication, May 24, 2004 , and in revised form, July 29, 2004.
* This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 596 (Molecular Mechanisms of Neurodegeneration) (to C. H. and H. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 49-89-2180-75-471/472; Fax: 49-89-2180-75-415; E-mail: chaass{at}med.uni-muenchen.de. 
To whom correspondence should be addressed. Tel.: 49-89-2180-75-480; Fax: 49-89-2180-75-415; E-mail: hsteiner{at}med.uni-muenchen.de.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Wakabayashi and B. De Strooper Presenilins: Members of the {gamma}-Secretase Quartets, But Part-Time Soloists Too Physiology, August 1, 2008; 23(4): 194 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Dejaegere, L. Serneels, M. K. Schafer, J. Van Biervliet, K. Horre, C. Depboylu, D. Alvarez-Fischer, A. Herreman, M. Willem, C. Haass, et al. Deficiency of Aph1B/C-{gamma}-secretase disturbs Nrg1 cleavage and sensorimotor gating that can be reversed with antipsychotic treatment PNAS, July 15, 2008; 105(28): 9775 - 9780. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sato, T. S. Diehl, S. Narayanan, S. Funamoto, Y. Ihara, B. De Strooper, H. Steiner, C. Haass, and M. S. Wolfe Active {gamma}-Secretase Complexes Contain Only One of Each Component J. Biol. Chem., November 23, 2007; 282(47): 33985 - 33993. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Clarke, I. Churcher, S. Ellis, J. D. J. Wrigley, H. D. Lewis, T. Harrison, M. S. Shearman, and D. Beher Intra- or Intercomplex Binding to the {gamma}-Secretase Enzyme: A MODEL TO DIFFERENTIATE INHIBITOR CLASSES J. Biol. Chem., October 20, 2006; 281(42): 31279 - 31289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Alves da Costa, C. Sunyach, R. Pardossi-Piquard, J. Sevalle, B. Vincent, N. Boyer, T. Kawarai, N. Girardot, P. St. George-Hyslop, and F. Checler Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer's disease. J. Neurosci., June 7, 2006; 26(23): 6377 - 6385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Wang, Y.-w. Zhang, X. Zhang, R. Liu, X. Zhang, S. Hong, K. Xia, J. Xia, Z. Zhang, and H. Xu Transcriptional regulation of APH-1A and increased {gamma}-secretase cleavage of APP and Notch by HIF-1 and hypoxia FASEB J, June 1, 2006; 20(8): 1275 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yamasaki, S. Eimer, M. Okochi, A. Smialowska, C. Kaether, R. Baumeister, C. Haass, and H. Steiner The GxGD motif of presenilin contributes to catalytic function and substrate identification of gamma-secretase. J. Neurosci., April 5, 2006; 26(14): 3821 - 3828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Krawitz, C. Haffner, R. Fluhrer, H. Steiner, B. Schmid, and C. Haass Differential Localization and Identification of a Critical Aspartate Suggest Non-redundant Proteolytic Functions of the Presenilin Homologues SPPL2b and SPPL3 J. Biol. Chem., November 25, 2005; 280(47): 39515 - 39523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Olry, P. Chastagner, A. Israel, and C. Brou Generation and Characterization of Mutant Cell Lines Defective in {gamma}-Secretase Processing of Notch and Amyloid Precursor Protein J. Biol. Chem., August 5, 2005; 280(31): 28564 - 28571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mastrangelo, P. M. Mathews, M. A. Chishti, S. D. Schmidt, Y. Gu, J. Yang, M. J. Mazzella, J. Coomaraswamy, P. Horne, B. Strome, et al. Dissociated phenotypes in presenilin transgenic mice define functionally distinct {gamma}-secretases PNAS, June 21, 2005; 102(25): 8972 - 8977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Urano, I. Hayashi, N. Isoo, P. C. Reid, Y. Shibasaki, N. Noguchi, T. Tomita, T. Iwatsubo, T. Hamakubo, and T. Kodama Association of active {gamma}-secretase complex with lipid rafts J. Lipid Res., May 1, 2005; 46(5): 904 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. J. Wrigley, I. Schurov, E. J. Nunn, A. C. L. Martin, E. E. Clarke, S. Ellis, T. P. Bonnert, M. S. Shearman, and D. Beher Functional Overexpression of {gamma}-Secretase Reveals Protease-independent Trafficking Functions and a Critical Role of Lipids for Protease Activity J. Biol. Chem., April 1, 2005; 280(13): 12523 - 12535. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Niimura, N. Isoo, N. Takasugi, M. Tsuruoka, K. Ui-Tei, K. Saigo, Y. Morohashi, T. Tomita, and T. Iwatsubo Aph-1 Contributes to the Stabilization and Trafficking of the {gamma}-Secretase Complex through Mechanisms Involving Intermolecular and Intramolecular Interactions J. Biol. Chem., April 1, 2005; 280(13): 12967 - 12975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Capell, D. Beher, S. Prokop, H. Steiner, C. Kaether, M. S. Shearman, and C. Haass {gamma}-Secretase Complex Assembly within the Early Secretory Pathway J. Biol. Chem., February 25, 2005; 280(8): 6471 - 6478. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Serneels, T. Dejaegere, K. Craessaerts, K. Horre, E. Jorissen, T. Tousseyn, S. Hebert, M. Coolen, G. Martens, A. Zwijsen, et al. Differential contribution of the three Aph1 genes to {gamma}-secretase activity in vivo PNAS, February 1, 2005; 102(5): 1719 - 1724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ma, T. Li, D. L. Price, and P. C. Wong APH-1a Is the Principal Mammalian APH-1 Isoform Present in {gamma}-Secretase Complexes during Embryonic Development J. Neurosci., January 5, 2005; 25(1): 192 - 198. [Abstract] [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 |
