title: Functional implications of the conformational switch in AICD peptide upon binding to Grb2-SH2 domain.
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.
authors: Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhan Nagar, WB, Kolkata 700 064, India.
authors: Samir
authors: S
authors: Das
authors: Mithu
authors: M
authors: Raychaudhuri
authors: Udayaditya
authors: U
authors: Sen
authors: Debashis
authors: D
authors: Mukhopadhyay
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D001483:Base Sequence; D018360:Crystallography, X-Ray; D017931:DNA Primers; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D018909:src Homology Domains
chemical_list: D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D010446:Peptide Fragments