C-terminal 37 residues of LRP promote the amyloidogenic processing of APP independent of FE65.
Write to authors to ask them to make this article freely available at NoL Archive
Lakshmana MK, Chen E, Yoon IS, Kang DE.
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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 2-hybrid screen using LRP-C37 region as bait reveal 4 new LRP-binding proteins implicated in intracellular signaling 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.
PMID: 18373737 [PubMed - as supplied by publisher]
PubMed ID and Record
Lakshmana MK, Chen E, Yoon IS, Kang DE.
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
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 2-hybrid screen using LRP-C37 region as bait reveal 4 new LRP-binding proteins implicated in intracellular signaling 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.
PMID: 18373737 [PubMed - as supplied by publisher]
PubMed ID and Record
posted by Shawna Cullen @ 3:40 AM
0 Comments:
Post a Comment
<< Home