HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 29, 27303-27309, July 22, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/29/27303    most recent M413969200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lleó, A. Articles by Berezovska, O. Search for Related Content PubMed PubMed Citation Articles by Lleó, A. Articles by Berezovska, O. Social Bookmarking                      What's this?

Low Density Lipoprotein Receptor-related Protein (LRP) Interacts with Presenilin 1 and Is a Competitive Substrate of the Amyloid Precursor Protein (APP) for -Secretase^*

Alberto Lleó, Elaine Waldron, Christine A. F. von Arnim, Lauren Herl, Michele M. Tangredi, Ithan D. Peltan, Dudley K. Strickland¶, Edward H. Koo||, Bradley T. Hyman, Claus U. Pietrzik**, and Oksana Berezovska**

From the Alzheimer Research Unit, Massachusetts Institute for Neurodegenerative Disorders, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the Department of Molecular Neurodegeneration, Institute for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University, 55099 Mainz, Germany, the ^¶Departments of Surgery and Physiology, University of Maryland School of Medicine, Rockville, Maryland 20855, and the ^||Department of Neurosciences, University of California San Diego, La Jolla, California 92093

Presenilin 1 (PS1) is a critical component of the -secretase complex, which is involved in the cleavage of several substrates including the amyloid precursor protein (APP) and the Notch receptor. Recently, the low density receptor-related protein (LRP) has been shown to be cleaved by a -secretase-like activity. We postulated that LRP may interact with PS1 and tested its role as a competitive substrate for -secretase. In this report we show that LRP colocalizes and interacts with endogenous PS1 using coimmunoprecipitation and fluorescence lifetime imaging microscopy. In addition, we found that -secretase active site inhibitors do not disrupt the interaction between LRP and PS1, suggesting that the substrate associates with a -secretase docking site located in close proximity to PS1. This is analogous to APP--secretase interactions. Finally, we show that LRP competes with APP for -secretase activity. Overexpression of a truncated LRP construct consisting of the C terminus, the transmembrane domain, and a short extracellular portion leads to a reduction in the levels of the A₄₀, A₄₂, and p3 peptides without changing the total level of APP expression. In addition, transfection with the -chain of LRP causes an increase in uncleaved APP C-terminal fragments and a concomitant decrease in the signaling effects of the APP intracellular domain. In conclusion, LRP is a PS1 interactor and can compete with APP for -secretase enzymatic activity.

Received for publication, December 13, 2004 , and in revised form, May 5, 2005.

^* This work was supported by a Hoffman Fellowship (to A. L.), Deutsche Forschungsgemeinschaft Grants AR 379/1.1 (to C. A. F. v. A.) and Pi379 (to C. U. P.), and National Institutes of Health Grants HL50784 (to D. K. S), AG12376 (to E .H. K.), AG15379, and AG12406 (to B. T. H.). 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.

^** These authors contributed equally to this work.

To whom correspondence may be addressed: Molecular Neurodegeneration, Rm. 04-128, Inst. for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg-University, 55099 Mainz, Germany. Tel.: 49-613-1392-5390; Fax: 49-613-1392-6488; E-mail: Pietrzik{at}uni-mainz.de.

To whom correspondence may be addressed: Alzheimer Research Unit, Rm. 2009, Massachusetts General Hospital, 114 16th St., Charlestown, MA 02129. Tel.: 617-726-1263; Fax: 617-724-1480; E-mail: oberezovska{at}partners.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I.-S. Yoon, E. Chen, T. Busse, E. Repetto, M. K. Lakshmana, E. H. Koo, and D. E. Kang Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway FASEB J, September 1, 2007; 21(11): 2742 - 2752. [Abstract] [Full Text] [PDF]

				C. Bohm, N. M. Seibel, B. Henkel, H. Steiner, C. Haass, and W. Hampe SorLA Signaling by Regulated Intramembrane Proteolysis J. Biol. Chem., May 26, 2006; 281(21): 14547 - 14553. [Abstract] [Full Text] [PDF]

				J. D. Best, M. T. Jay, F. Otu, I. Churcher, M. Reilly, P. Morentin-Gutierrez, C. Pattison, T. Harrison, M. S. Shearman, and J. R. Atack In Vivo Characterization of Abeta(40) Changes in Brain and Cerebrospinal Fluid Using the Novel {gamma}-Secretase Inhibitor N-[cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the Rat J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 786 - 790. [Abstract] [Full Text] [PDF]