title: C-terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65.
abstract: The major defining pathological hallmark of Alzheimer's disease (AD) is the accumulation of amyloid beta protein (Abeta), a small peptide derived from beta- and gamma-secretase cleavages of the amyloid precursor protein (APP). Recent studies have shown that the Low-density lipoprotein receptor-related protein (LRP) plays a pivotal role in the trafficking of APP and generation of Abeta. In particular, we recently showed that the soluble cytoplasmic tail of LRP (LRP-ST) without a membrane tether was sufficient to promote Abeta generation. In this study, we demonstrate that the last 37 residues of LRP cytoplasmic tail (LRP-C37) lacking the NPxY motifs and FE65 binding mediate the core pro-amyloidogenic activity of LRP-ST. Moreover, we show that the conserved dileucine motif within the LRP-C37 region is a key determinant of its Abeta promoting activity. Finally, results from a yeast two-hybrid screen using LRP-C37 region as bait reveal four new LRP-binding proteins implicated in intracellular signalling and membrane protein trafficking. Our findings indicate that the LRP-C37 sequence represents a new protein-binding domain that may be useful as a therapeutic target and tool to lower Abeta generation in AD.
authors: Department of Neurosciences, University of California, San Diego, Gilman Drive, La Jolla, CA 92093, USA.
authors: Madepalli K
authors: MK
authors: Lakshmana
authors: Eunice
authors: E
authors: Chen
authors: Il-Sang
authors: IS
authors: Yoon
authors: David E
authors: DE
authors: Kang
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D047468:Immunoprecipitation; D007930:Leucine / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals; D013329:Structure-Activity Relationship; D020798:Two-Hybrid System Techniques
chemical_list: C091042:APBB1 protein, human; D016564:Amyloid beta-Protein Precursor; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D007930:Leucine