The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate.
BACE is a transmembrane protease with beta-secretase activity that cleaves the amyloid precursor protein (APP). After BACE cleavage, APP becomes a substrate for gamma-secretase, leading to release of amyloid-beta peptide (Abeta), which accumulates in senile plaques in Alzheimer disease. APP and BACE are co-internalized from the cell surface to early endosomes. APP is also known to interact at the cell surface and be internalized by the low density lipoprotein receptor-related protein (LRP), a multifunctional endocytic and signaling receptor. Using a new fluorescence resonance energy transfer (FRET)-based assay of protein proximity, fluorescence lifetime imaging (FLIM), and co-immunoprecipitation we demonstrate that the light chain of LRP interacts with BACE on the cell surface in association with lipid rafts. Surprisingly, the BACE-LRP interaction leads to an increase in LRP C-terminal fragment, release of secreted LRP in the media and subsequent release of the LRP intracellular domain from the membrane. Taken together, these data suggest that there is a close interaction between BACE and LRP on the cell surface, and that LRP is a novel BACE substrate.
von Arnim
Christine A F
CA
Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Kinoshita
Ayae
A
Peltan
Ithan D
ID
Tangredi
Michelle M
MM
Herl
Lauren
L
Lee
Bonny M
BM
Spoelgen
Robert
R
Hshieh
Tammy T
TT
Ranganathan
Sripriya
S
Battey
Frances D
FD
Liu
Chun-Xiang
CX
Bacskai
Brian J
BJ
Sever
Sanja
S
Irizarry
Michael C
MC
Strickland
Dudley K
DK
Hyman
Bradley T
BT
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D010450:Endopeptidases; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D013379:Substrate Specificity / Q000502:physiology
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse