Sequence-specific recognition of the internalization motif of the Alzheimer's amyloid precursor protein by the X11 PTB domain.
The crystal structure of the phosphotyrosine-binding domain (PTB) of the X11 protein has been determined, in complex with unphosphorylated peptides corresponding to a region of beta-amyloid precursor protein (betaAPP) that is required for receptor internalization. The mode of binding to X11 of the unphosphorylated peptides, which contain an NPxY motif, resembles that of phosphorylated peptides bound to the Shc and IRS-1 PTB domains. Eight peptide residues make specific contacts with the X11 PTB domain, and they collectively achieve high affinity (KD = 0.32 microM) and specificity. These results suggest that, in contrast to the SH2 domains, the PTB domains are primarily peptide-binding domains that have, in some cases, acquired specificity for phosphorylated tyrosines.
Zhang
Z
Z
Department of Pharmacology, New York University Medical Center, 550 First Avenue, New York, NY 10016, USA.
Lee
C H
CH
Mandiyan
V
V
Borg
J P
JP
Margolis
B
B
Schlessinger
J
J
Kuriyan
J
J
D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D019000:Phosphotyrosine / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D019000:Phosphotyrosine; D014443:Tyrosine