XB51 isoforms mediate Alzheimer's beta-amyloid peptide production by X11L (X11-like protein)-dependent and -independent mechanisms.
XB51 (derived from X11-like binding protein of clone number 51) was isolated by yeast two-hybrid cDNA screening using the N-terminal domain of X11L (X11-like protein) as a bait. X11L is a neuron-specific adaptor protein that is known to down-regulate APP (beta-amyloid precursor protein) metabolism by associating with the cytoplasmic domain of APP, but the detailed mechanisms are still unknown. Thus the X11L-associated protein XB51 is believed to regulate APP metabolism by modifying X11L function through its interaction with X11L. Here we report that the hXB51 (human XB51 ) gene can yield two transcripts, one with exon 9 spliced out (resulting in the hXB51beta isoform) and the other containing exon 9 (yielding the hXB51alpha isoform). hXB51alpha binds to X11L to form a tripartite complex composed of hXB51alpha, X11L and APP. Complex-formation results in blocking X11L's suppression of Abeta (beta-amyloid) generation from APP. hXB51beta associates with X11L and inhibits its interaction with APP. However, hXB51beta suppresses Abeta generation and secretion in an X11L-independent manner. Thus the hXB51 isoforms regulate Abeta generation differently, either enhancing it by modifying the association of X11L with APP or suppressing it in an X11L-independent manner. These observations advance our understanding of the molecular mechanisms regulating intracellular Abeta production and the pathogenesis of Alzheimer's disease.
Sumioka
Akio
A
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
Imoto
Seiyu
S
Martins
Ralph N
RN
Kirino
Yutaka
Y
Suzuki
Toshiharu
T
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics*; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary; D005786:Gene Expression Regulation; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
C079091:APBA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D017931:DNA Primers; D018076:DNA, Complementary; C412571:NECAB3 protein, human; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins