title: The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate.
abstract: 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.
authors.affiliation: Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
authors.forename: Christine A F
authors.initials: CA
authors.lastname: von Arnim
authors.forename: Ayae
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Ithan D
authors.initials: ID
authors.lastname: Peltan
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Tangredi
authors.forename: Lauren
authors.initials: L
authors.lastname: Herl
authors.forename: Bonny M
authors.initials: BM
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Spoelgen
authors.forename: Tammy T
authors.initials: TT
authors.lastname: Hshieh
authors.forename: Sripriya
authors.initials: S
authors.lastname: Ranganathan
authors.forename: Frances D
authors.initials: FD
authors.lastname: Battey
authors.forename: Chun-Xiang
authors.initials: CX
authors.lastname: Liu
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.forename: Sanja
authors.initials: S
authors.lastname: Sever
authors.forename: Michael C
authors.initials: MC
authors.lastname: Irizarry
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: 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
chemical_list: 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