3MXY

Structures of Grb2-SH2 Domain and AICD peptide Complexes Reveal a Conformational Switch and Their Functional Implications.

Summary for 3MXY

• Entry DOI: 10.2210/pdb3mxy/pdb
• Related: 1JYQ 1JYR 3KFJ 3MXC
• Descriptor: Growth factor receptor-bound protein 2, AICD peptide E683V variant (3 entities in total)
• Functional Keywords: protein-peptide complex, aicd, grb2-sh2, protein binding, alzheimer's disease, app
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P62993
• Total number of polymer chains: 2
• Total formula weight: 12864.38

Authors

Sen, U.,Das, S. (deposition date: 2010-05-08, release date: 2011-05-11, Last modification date: 2024-11-27)

Primary citation

Das, S.,Raychaudhuri, M.,Sen, U.,Mukhopadhyay, D.
Functional Implications of the Conformational Switch in AICD Peptide upon Binding to Grb2-SH2 Domain.
J.Mol.Biol., 414:217-230, 2011

PubMed 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.

PubMed: 22001015
DOI: 10.1016/j.jmb.2011.09.046

Experimental method

X-RAY DIFFRACTION (2.3 Å)