| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 273, Issue 6, 3205-3211, February 6, 1998
,,,
,
From the Mutations in the presenilin (PS) genes are linked
to early onset familial Alzheimer's disease (FAD). PS-1 proteins are
proteolytically processed by an unknown protease to two stable
fragments of ~30 kDa (N-terminal fragment (NTF)) and ~20 kDa
(C-terminal fragment (CTF)) (Thinakaran, G., Borchelt, D. R., Lee,
M. K., Slunt, H. H., Spitzer, L., Kim, G., Ratovitsky, T.,
Davenport, F., Nordstedt, C., Seeger, M., Hardy, J., Levey, A. I.,
Gandy, S. E., Jenkins, N. A., Copeland, N. G., Price,
D. L., and Sisodia, S. S. (1996) Neuron 17, 181-190). Here we show that the CTF and NTF of PS-1 bind to each
other. Fractionating proteins from
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid-extracted membrane preparations by velocity sedimentation reveal a high molecular mass SDS and Triton X-100-sensitive complex of
approximately 100-150 kDa. To prove if both proteolytic fragments of
PS-1 are bound to the same complex, we performed
co-immunoprecipitations using multiple antibodies specific to the CTF
and NTF of PS-1. These experiments revealed that both fragments of PS-1
occur as a tightly bound non-covalent complex. Upon overexpression,
unclipped wild type PS-1 sediments at a lower molecular weight in
glycerol velocity gradients than the endogenous fragments. In contrast, the non-cleavable, FAD-associated PS-1 Central Institute of Mental Health, New York University
Medical Center, Department of Psychiatry,
Orangeburg, New York 10962
exon 9 sediments at a molecular weight similar to that observed for the endogenous
proteolytic fragments. This result may indicate that the exon 9 mutation generates a mutant protein that exhibits biophysical
properties similar to the naturally occurring PS-1 fragments. This
could explain the surprising finding that the exon 9 mutation is
functionally active, although it cannot be proteolytically processed
(Baumeister, R., Leimer, U., Zweckbronner, I., Jakubek, C.,
Grünberg, J., and Haass, C. (1997) Genes & Function
1, 149-159; Levitan, D., Doyle, T., Brousseau, D., Lee, M.,
Thinakaran, G., Slunt, H., Sisodia, S., and Greenwald, I. (1996)
Proc. Natl. Acad. Sci. U. S. A. 93, 14940-14944).
Formation of a high molecular weight complex of PS-1 composed of both
endogenous PS-1 fragments may also explain the recent finding that
FAD-associated mutations within the N-terminal portion of PS-1 result
in the hyperaccumulation not only of the NTF but also of the CTF (Lee,
M. K., Borchelt, D. R., Kim, G., Thinakaran, G., Slunt, H. H., Ratovitski, T., Martin, L. J., Kittur, A., Gandy, S., Levey,
A. I., Jenkins, N., Copeland, N., Price, D. L., and Sisodia, S. S. (1997) Nat. Med. 3, 756-760). Moreover, these results
provide a model to understand the highly regulated expression and
processing of PS proteins.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M.-X. Silveyra, G. Evin, M.-F. Montenegro, C. J. Vidal, S. Martinez, J. G. Culvenor, and J. Saez-Valero Presenilin 1 Interacts with Acetylcholinesterase and Alters Its Enzymatic Activity and Glycosylation Mol. Cell. Biol., May 1, 2008; 28(9): 2908 - 2919. [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]
|
|
|
|
|
|
K. Prager, L. Wang-Eckhardt, R. Fluhrer, R. Killick, E. Barth, H. Hampel, C. Haass, and J. Walter A Structural Switch of Presenilin 1 by Glycogen Synthase Kinase 3beta-mediated Phosphorylation Regulates the Interaction with beta-Catenin and Its Nuclear Signaling J. Biol. Chem., May 11, 2007; 282(19): 14083 - 14093. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Haffner, U. Dettmer, T. Weiler, and C. Haass The Nicastrin-like Protein Nicalin Regulates Assembly and Stability of the Nicalin-Nodal Modulator (NOMO) Membrane Protein Complex J. Biol. Chem., April 6, 2007; 282(14): 10632 - 10638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-F. Liao, B.-J. Wang, W.-M. Hsu, H. Lee, C.-Y. Liao, S.-Y. Wu, H.-T. Cheng, and M.-K. Hu Unnatural Amino Acid-Substituted (Hydroxyethyl)urea Peptidomimetics Inhibit {gamma}-Secretase and Promote the Neuronal Differentiation of Neuroblastoma Cells Mol. Pharmacol., February 1, 2007; 71(2): 588 - 601. [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]
|
|
|
|
|
|
I. Jutras, A. Laplante, J. Boulais, S. Brunet, G. Thinakaran, and M. Desjardins {gamma}-Secretase Is a Functional Component of Phagosomes J. Biol. Chem., October 28, 2005; 280(43): 36310 - 36317. [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]
|
|
|
|
 |
|
 O. Berezovska, A. Lleo, L. D. Herl, M. P. Frosch, E. A. Stern, B. J. Bacskai, and B. T. Hyman Familial Alzheimer's Disease Presenilin 1 Mutations Cause Alterations in the Conformation of Presenilin and Interactions with Amyloid Precursor Protein J. Neurosci., March 16, 2005; 25(11): 3009 - 3017. [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]
|
|
|
|
|
|
K. Shirotani, D. Edbauer, S. Prokop, C. Haass, and H. Steiner Identification of Distinct {gamma}-Secretase Complexes with Different APH-1 Variants J. Biol. Chem., October 1, 2004; 279(40): 41340 - 41345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, W.-j. Luo, Y.-w. Zhang, Y.-M. Li, G. Thinakaran, P. Greengard, and H. Xu Presenilins and {gamma}-Secretase Inhibitors Affect Intracellular Trafficking and Cell Surface Localization of the {gamma}-Secretase Complex Components J. Biol. Chem., September 24, 2004; 279(39): 40560 - 40566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Edbauer, C. Kaether, H. Steiner, and C. Haass Co-expression of Nicastrin and Presenilin Rescues a Loss of Function Mutant of APH-1 J. Biol. Chem., September 3, 2004; 279(36): 37311 - 37315. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Wolfe and R. Kopan Intramembrane Proteolysis: Theme and Variations Science, August 20, 2004; 305(5687): 1119 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Laudon, H. Karlstrom, P. M. Mathews, M. R. Farmery, S. E. Gandy, J. Lundkvist, U. Lendahl, and J. Naslund Functional Domains in Presenilin 1: THE TYR-288 RESIDUE CONTROLS {gamma}-SECRETASE ACTIVITY AND ENDOPROTEOLYSIS J. Biol. Chem., June 4, 2004; 279(23): 23925 - 23932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fluhrer, A. Friedlein, C. Haass, and J. Walter Phosphorylation of Presenilin 1 at the Caspase Recognition Site Regulates Its Proteolytic Processing and the Progression of Apoptosis J. Biol. Chem., January 16, 2004; 279(3): 1585 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Capell, C. Kaether, D. Edbauer, K. Shirotani, S. Merkl, H. Steiner, and C. Haass Nicastrin Interacts with {gamma}-Secretase Complex Components via the N-terminal Part of Its Transmembrane Domain J. Biol. Chem., December 26, 2003; 278(52): 52519 - 52523. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Aguzzi and C. Haass Games Played by Rogue Proteins in Prion Disorders and Alzheimer's Disease Science, October 31, 2003; 302(5646): 814 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. LaVoie, P. C. Fraering, B. L. Ostaszewski, W. Ye, W. T. Kimberly, M. S. Wolfe, and D. J. Selkoe Assembly of the {gamma}-Secretase Complex Involves Early Formation of an Intermediate Subcomplex of Aph-1 and Nicastrin J. Biol. Chem., September 26, 2003; 278(39): 37213 - 37222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Kim, T. Ikeuchi, C. Yu, and S. S. Sisodia Regulated Hyperaccumulation of Presenilin-1 and the "{gamma}-Secretase" Complex: EVIDENCE FOR DIFFERENTIAL INTRAMEMBRANOUS PROCESSING OF TRANSMEMBRANE SUBSTRATES J. Biol. Chem., September 5, 2003; 278(36): 33992 - 34002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. LaVoie and D. J. Selkoe The Notch Ligands, Jagged and Delta, Are Sequentially Processed by {alpha}-Secretase and Presenilin/{gamma}-Secretase and Release Signaling Fragments J. Biol. Chem., September 5, 2003; 278(36): 34427 - 34437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Marques, U. Keil, A. Bonert, B. Steiner, C. Haass, W. E. Muller, and A. Eckert Neurotoxic Mechanisms Caused by the Alzheimer's Disease-linked Swedish Amyloid Precursor Protein Mutation: OXIDATIVE STRESS, CASPASES, AND THE JNK PATHWAY J. Biol. Chem., July 18, 2003; 278(30): 28294 - 28302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xia and M. S. Wolfe Intramembrane proteolysis by presenilin and presenilin-like proteases J. Cell Sci., July 15, 2003; 116(14): 2839 - 2844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. R. Farmery, L. O. Tjernberg, S. E. Pursglove, A. Bergman, B. Winblad, and J. Naslund Partial Purification and Characterization of {gamma}-Secretase from Post-mortem Human Brain J. Biol. Chem., June 27, 2003; 278(27): 24277 - 24284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lakowski, S. Eimer, C. Gobel, A. Bottcher, B. Wagler, and R. Baumeister Two suppressors of sel-12 encode C2H2 zinc-finger proteins that regulate presenilin transcription in Caenorhabditis elegans Development, May 15, 2003; 130(10): 2117 - 2128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Huse, D. Byant, Y. Yang, D. S. Pijak, I. D'Souza, J. J. Lah, V. M.-Y. Lee, R. W. Doms, and D. G. Cook Endoproteolysis of beta -Secretase (beta -Site Amyloid Precursor Protein-cleaving Enzyme) within Its Catalytic Domain. A POTENTIAL MECHANISM FOR REGULATION J. Biol. Chem., May 2, 2003; 278(19): 17141 - 17149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. V. Gassen and W. Annaert Amyloid, Presenilins, and Alzheimer's Disease Neuroscientist, April 1, 2003; 9(2): 117 - 126. [Abstract] [PDF]
|
|
|
|
 |
|
 M. S. Wolfe {gamma}-Secretase--Intramembrane Protease with a Complex Sci. Aging Knowl. Environ., March 19, 2003; 2003(11): pe7 - 7. [Abstract] [Full Text]
|
|
|
|
|
|
W.-j. Luo, H. Wang, H. Li, B. S. Kim, S. Shah, H.-J. Lee, G. Thinakaran, T.-W. Kim, G. Yu, and H. Xu PEN-2 and APH-1 Coordinately Regulate Proteolytic Processing of Presenilin 1 J. Biol. Chem., February 28, 2003; 278(10): 7850 - 7854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Gu, F. Chen, N. Sanjo, T. Kawarai, H. Hasegawa, M. Duthie, W. Li, X. Ruan, A. Luthra, H. T. J. Mount, et al. APH-1 Interacts with Mature and Immature Forms of Presenilins and Nicastrin and May Play a Role in Maturation of Presenilin{middle dot}Nicastrin Complexes J. Biol. Chem., February 21, 2003; 278(9): 7374 - 7380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fluhrer, G. Multhaup, A. Schlicksupp, M. Okochi, M. Takeda, S. Lammich, M. Willem, G. Westmeyer, W. Bode, J. Walter, et al. Identification of a beta -Secretase Activity, Which Truncates Amyloid beta -Peptide after Its Presenilin-dependent Generation J. Biol. Chem., February 14, 2003; 278(8): 5531 - 5538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Lammich, M. Okochi, M. Takeda, C. Kaether, A. Capell, A.-K. Zimmer, D. Edbauer, J. Walter, H. Steiner, and C. Haass Presenilin-dependent Intramembrane Proteolysis of CD44 Leads to the Liberation of Its Intracellular Domain and the Secretion of an Abeta -like Peptide J. Biol. Chem., November 15, 2002; 277(47): 44754 - 44759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Steiner, E. Winkler, D. Edbauer, S. Prokop, G. Basset, A. Yamasaki, M. Kostka, and C. Haass PEN-2 Is an Integral Component of the gamma -Secretase Complex Required for Coordinated Expression of Presenilin and Nicastrin J. Biol. Chem., October 11, 2002; 277(42): 39062 - 39065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Suh and F. Checler Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease Pharmacol. Rev., September 1, 2002; 54(3): 469 - 525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Tian, C. D. Sobotka-Briner, J. Zysk, X. Liu, C. Birr, M. A. Sylvester, P. D. Edwards, C. D. Scott, and B. D. Greenberg Linear Non-competitive Inhibition of Solubilized Human gamma -Secretase by Pepstatin A Methylester, L685458, Sulfonamides, and Benzodiazepines J. Biol. Chem., August 23, 2002; 277(35): 31499 - 31505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Kaether, S. Lammich, D. Edbauer, M. Ertl, J. Rietdorf, A. Capell, H. Steiner, and C. Haass Presenilin-1 affects trafficking and processing of {beta}APP and is targeted in a complex with nicastrin to the plasma membrane J. Cell Biol., August 5, 2002; 158(3): 551 - 561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-S. Yang, A. Tandon, F. Chen, G. Yu, H. Yu, S. Arawaka, H. Hasegawa, M. Duthie, S. D. Schmidt, T. V. Ramabhadran, et al. Mature Glycosylation and Trafficking of Nicastrin Modulate Its Binding to Presenilins J. Biol. Chem., July 26, 2002; 277(31): 28135 - 28142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Edbauer, E. Winkler, C. Haass, and H. Steiner Presenilin and nicastrin regulate each other and determine amyloid beta -peptide production via complex formation PNAS, June 25, 2002; 99(13): 8666 - 8671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Huse, K. Liu, D. S. Pijak, D. Carlin, V. M.-Y. Lee, and R. W. Doms beta -Secretase Processing in the Trans-Golgi Network Preferentially Generates Truncated Amyloid Species That Accumulate in Alzheimer's Disease Brain J. Biol. Chem., May 3, 2002; 277(18): 16278 - 16284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Morohashi, N. Hatano, S. Ohya, R. Takikawa, T. Watabiki, N. Takasugi, Y. Imaizumi, T. Tomita, and T. Iwatsubo Molecular Cloning and Characterization of CALP/KChIP4, a Novel EF-hand Protein Interacting with Presenilin 2 and Voltage-gated Potassium Channel Subunit Kv4 J. Biol. Chem., April 19, 2002; 277(17): 14965 - 14975. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. P. Esler, W. T. Kimberly, B. L. Ostaszewski, W. Ye, T. S. Diehl, D. J. Selkoe, and M. S. Wolfe Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate PNAS, February 20, 2002; (2002) 52436599. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-H. Kim, J. Y. Leem, J. J. Lah, H. H. Slunt, A. I. Levey, G. Thinakaran, and S. S. Sisodia Multiple Effects of Aspartate Mutant Presenilin 1 on the Processing and Trafficking of Amyloid Precursor Protein J. Biol. Chem., November 9, 2001; 276(46): 43343 - 43350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Levitan, J. Lee, L. Song, R. Manning, G. Wong, E. Parker, and L. Zhang PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling PNAS, September 26, 2001; (2001) 211321898. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. P. Esler and M. S. Wolfe A Portrait of Alzheimer Secretases--New Features and Familiar Faces Science, August 24, 2001; 293(5534): 1449 - 1454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. A. Mann, S. M. Pickering-Brown, A. Takeuchi, and T. Iwatsubo Amyloid Angiopathy and Variability in Amyloid {beta} Deposition Is Determined by Mutation Position in Presenilin-1-Linked Alzheimer's Disease Am. J. Pathol., June 1, 2001; 158(6): 2165 - 2175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Selkoe Alzheimer's Disease: Genes, Proteins, and Therapy Physiol Rev, April 1, 2001; 81(2): 741 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pigino, A. Pelsman, H. Mori, and J. Busciglio Presenilin-1 Mutations Reduce Cytoskeletal Association, Deregulate Neurite Growth, and Potentiate Neuronal Dystrophy and Tau Phosphorylation J. Neurosci., February 1, 2001; 21(3): 834 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. ANNAERT, P. CUPERS, P. SAFTIG, and B. DE STROOPER Presenilin Function in APP Processing Ann. N.Y. Acad. Sci., December 1, 2000; 920(1): 158 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Xia, W. J. Ray, B. L. Ostaszewski, T. Rahmati, W. T. Kimberly, M. S. Wolfe, J. Zhang, A. M. Goate, and D. J. Selkoe Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta -protein generation PNAS, August 1, 2000; 97(16): 9299 - 9304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shirotani, K. Takahashi, W. Araki, K. Maruyama, and T. Tabira Mutational Analysis of Intrinsic Regions of Presenilin 2 That Determine Its Endoproteolytic Cleavage and Pathological Function J. Biol. Chem., February 4, 2000; 275(5): 3681 - 3686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tomita, R. Takikawa, A. Koyama, Y. Morohashi, N. Takasugi, T. C. Saido, K. Maruyama, and T. Iwatsubo C Terminus of Presenilin Is Required for Overproduction of Amyloidogenic Abeta 42 through Stabilization and Endoproteolysis of Presenilin J. Neurosci., December 15, 1999; 19(24): 10627 - 10634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jacobsen, D. Reinhardt, M. Brockhaus, D. Bur, C. Kocyba, H. Kurt, M. G. Grim, R. Baumeister, and H. Loetscher The Influence of Endoproteolytic Processing of Familial Alzheimer's Disease Presenilin 2 on Abeta 42 Amyloid Peptide Formation J. Biol. Chem., December 3, 1999; 274(49): 35233 - 35239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. G. Annaert, L. Levesque, K. Craessaerts, I. Dierinck, G. Snellings, D. Westaway, P. St. George-Hyslop, B. Cordell, P. Fraser, and B. De Strooper Presenilin 1 Controls {gamma}-Secretase Processing of Amyloid Precursor Protein in Pre-Golgi Compartments of Hippocampal Neurons J. Cell Biol., October 18, 1999; 147(2): 277 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Imafuku, T. Masaki, M. Waragai, S. Takeuchi, M. Kawabata, S.-i. Hirai, S. Ohno, L.E. Nee, C.F. Lippa, I. Kanazawa, et al. Presenilin 1 Suppresses the Function of c-Jun Homodimers via Interaction with QM/Jif-1 J. Cell Biol., October 4, 1999; 147(1): 121 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
