PDBsum entry 3mxc

Protein binding

PDB id: 3mxc

Contents

Protein chain

98 a.a.

Ligands

GLY-PTR-GLU-ASN-PRO-THR-TYR

Waters ×122

PDB id:

3mxc

Name:

Protein binding

Title:

Structures of grb2-sh2 domain and aicd peptide complexes reveal a conformational switch and their functional implications.

Structure:

Growth factor receptor-bound protein 2. Chain: a. Synonym: adapter protein grb2, sh2/sh3 adapter grb2, protein ash. Engineered: yes. Aicd peptide. Chain: l. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: grb2, ash. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes

Resolution:

2.00Å R-factor: 0.217 R-free: 0.244

Authors:

U.Sen,S.Das

Key ref:

S.Das et al. (2011). Functional implications of the conformational switch in AICD peptide upon binding to Grb2-SH2 domain. J Mol Biol, 414, 217-230. PubMed id: 22001015

Date:

07-May-10 Release date: 11-May-11

Protein chain

P62993  (GRB2_HUMAN) -  Growth factor receptor-bound protein 2 from Homo sapiens

Seq: 217 a.a.

Struc: 98 a.a.

J Mol Biol 414:217-230 (2011)

PubMed id: 22001015

Functional implications of the conformational switch in AICD peptide upon binding to Grb2-SH2 domain.

S.Das, M.Raychaudhuri, U.Sen, D.Mukhopadhyay.

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.