کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2184870 | 1095943 | 2011 | 14 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Functional Implications of the Conformational Switch in AICD Peptide upon Binding to Grb2-SH2 Domain Functional Implications of the Conformational Switch in AICD Peptide upon Binding to Grb2-SH2 Domain](/preview/png/2184870.png)
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.
Graphical AbstractFigure optionsDownload high-quality image (182 K)Download as PowerPoint slideResearch Highlights
► Crystal structures of tyrosine-phosphorylated AICD nona-peptides complexed with Grb2-SH2 domain are determined.
► Specific proline residue in AICD is responsible for the unique binding mode with the Grb2-SH2 domain.
► Phosphorylation dependent conformational switch of AICD upon binding to Grb2-SH2 domain is evident.
Journal: Journal of Molecular Biology - Volume 414, Issue 2, 25 November 2011, Pages 217–230