Interaction of a Neuron-specific Protein Containing PDZ Domains with Alzheimer's Amyloid Precursor Protein

Susumu Tomita,Toshinori Ozaki,Hidenori Taru,Shinobu Oguchi,Shizu Takeda,Yoshimasa Yagi,Shigeru Sakiyama,Yutaka Kirino,Toshiharu Suzuki

doi:10.1074/jbc.274.4.2243

Abstract

A novel protein, human X11-like (human X11L), contains a phosphotyrosine interaction (PI) domain and two PDZ domains and displays 55.2% amino acid homology with the human X11 (human X11). The PI domain of human X11L interacts with a sequence containing the NPXY motif found in the cytoplasmic domain of Alzheimer's amyloid precursor protein. A construct lacking the carboxyl-terminal domain, which comprises two PDZ domains (N + PI), enhances PI binding to APP, whereas another construct lacking an amino-terminal domain relative to PI domain (PI + C) suppresses PI binding to APP. Overexpression of full-length human X11L (N + PI + C) in cells that express APP695 stably decreased the secretion of Abeta40 but not that of Abeta42. However, overexpression of the PI domain alone and the N + PI construct in cells did not affect the secretion of Abeta despite their ability to bind to the cytoplasmic domain of Alzheimer's amyloid precursor protein. These observations suggest that the amino-terminal domain regulates PI binding to APP and that the carboxyl-terminal domain containing PDZ motifs is essential to modulate APP processing. Because expression of the human X11L gene is specific to brain, the present observations should contribute to shedding light on the molecular mechanism of APP processing in Alzheimer's disease.

Highlights

A novel protein, human X11-like, contains a phosphotyrosine interaction (PI) domain and two PDZ domains and displays 55.2% amino acid homology with the human X11
We found that human X11like protein (X11L) requires a sequence containing the NPXY motif of APPCOOH for amyloid precursor protein (APP) binding and that association of the PI domain with APP was suppressed by a deletion of a amino-terminal domain fused to the PI domain (PI ϩ C construct) but enhanced by a deletion of a carboxyl-terminal domain fused to the PI domain (N ϩ PI construct)
Molecular Cloning of a cDNA Encoding Human X11L Protein: Primary Structure and Chromosome Location—The short cytoplasmic domain of APP is the sole region exposed to the cytoplasm and contains several functional amino acid motifs that regulate the metabolism of APP [13,14,15, 30, 31]

Summary

Introduction

A novel protein, human X11-like (human X11L), contains a phosphotyrosine interaction (PI) domain and two PDZ domains and displays 55.2% amino acid homology with the human X11 (human X11). Another polyclonal anti-X11L carboxyl-terminal domain antibody, UT30, was raised against the peptide “Cys” plus containing the amino acid sequence between positions 735 and 749 of human X11L.

Results

Conclusion