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

6533b855fe1ef96bd12affe8

RESEARCH PRODUCT

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

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

subject

Immunoprecipitation Notch signaling pathway Mice Transgenic Binding Competitive Biochemistry Presenilin Cell Line Substrate Specificity Rats Sprague-Dawley Amyloid beta-Protein Precursor Mice Endopeptidases mental disorders Presenilin-1 Amyloid precursor protein Animals Aspartic Acid Endopeptidases Humans Binding site Molecular Biology Brain Chemistry Binding Sites biology Chemistry Membrane Proteins Cell Biology Rats nervous system diseases Cell biology Transmembrane domain Biochemistry Multiprotein Complexes LDL receptor biology.protein lipids (amino acids peptides and proteins)Amyloid Precursor Protein Secretases Amyloid precursor protein secretase Low Density Lipoprotein Receptor-Related Protein-1

description

Presenilin 1 (PS1) is a critical component of the gamma-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 gamma-secretase-like activity. We postulated that LRP may interact with PS1 and tested its role as a competitive substrate for gamma-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 gamma-secretase active site inhibitors do not disrupt the interaction between LRP and PS1, suggesting that the substrate associates with a gamma-secretase docking site located in close proximity to PS1. This is analogous to APP-gamma-secretase interactions. Finally, we show that LRP competes with APP for gamma-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 Abeta40, Abeta42, and p3 peptides without changing the total level of APP expression. In addition, transfection with the beta-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 gamma-secretase enzymatic activity.

year	journal	country	edition	language
2005-05-27	Journal of Biological Chemistry

https://doi.org/10.1074/jbc.m413969200