Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
Abstract
It has been hypothesized previously that synergistic effect of both amyloid
precursor protein intracellular C-terminal domain (AICD) and Aβ aggregation
could contribute to Alzheimer's disease pathogenesis. Structural studies of AICD
have found no stable globular fold over a broad range of pH. Present work is
based on the premises that a conformational switch involving the flipping of
C-terminal helix of AICD would be essential for effective binding with the Src
homology 2 (SH2) domain of growth factor receptor binding protein-2 (Grb2) and
subsequent initiation of Grb2-mediated endo-lysosomal pathway. High-resolution
crystal structures of Grb2-SH2 domain bound to AICD peptides reveal a unique
mode of binding where the peptides assume a noncanonical conformation that is
unlike other structures of AICD peptides bound to protein-tyrosine-binding
domains or that of its free state; rather, a flipping of the C-terminal helix of
AICD is evident. The involvement of different AICD residues in Grb2-SH2
interaction is further elucidated through fluorescence-based assays. Our results
reveal the significance of a specific interaction of the two molecules to
optimize the rapid transport of AICD inside endosomal vesicles presumably to
reduce the cytotoxic load.
