C-terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65.
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.
Lakshmana
Madepalli K
MK
Department of Neurosciences, University of California, San Diego, Gilman Drive, La Jolla, CA 92093, USA.
Chen
Eunice
E
Yoon
Il-Sang
IS
Kang
David E
DE
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
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