Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for gamma-secretase.
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.
Lleó
Alberto
A
Alzheimer Research Unit, Massachusetts Institute for Neurodegenerative Disorders, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Waldron
Elaine
E
von Arnim
Christine A F
CA
Herl
Lauren
L
Tangredi
Michele M
MM
Peltan
Ithan D
ID
Strickland
Dudley K
DK
Koo
Edward H
EH
Hyman
Bradley T
BT
Pietrzik
Claus U
CU
Berezovska
Oksana
O
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D001923:Brain Chemistry; D002460:Cell Line; D010450:Endopeptidases; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D053764:Presenilin-1; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse