Solution structure and ligand-binding site of the carboxy-terminal SH3 domain of GRB2.
BACKGROUND
Growth factor receptor-bound protein 2 (GRB2) is an adaptor protein with three Src homology (SH) domains in the order SH3-SH2-SH3. Both SH3 domains of GRB2 are necessary for interaction with the protein Son of sevenless (Sos), which acts as a Ras activator. Thus, GRB2 mediates signal transduction from growth factor receptors to Ras and is thought to be a key molecule in signal transduction.


RESULTS
The three-dimensional structure of the carboxy-terminal SH3 domain of GRB2 (GRB2 C-SH3) was determined by NMR spectroscopy. The SH3 structure consists of six beta-strands arranged in two beta-sheets that are packed together perpendicularly with two additional beta-strands forming the third beta-sheet. GRB2 C-SH3 is very similar to SH3 domains from other proteins. The binding site of the ligand peptide (VPP-PVPPRRR) derived from the Sos protein was mapped on the GRB2 C-SH3 domain indirectly using 1H and 15N chemical shift changes, and directly using several intermolecular nuclear Overhauser effects.


CONCLUSIONS
Despite the structural similarity among the known SH3 domains, the sequence alignment and the secondary structure assignments differ. We therefore propose a standard description of the SH3 structures to facilitate comparison of individual SH3 domains, based on their three-dimensional structures. The binding site of the ligand peptide on GRB2 C-SH3 is in good agreement with those found in other SH3 domains.
Kohda
D
D
Department of Molecular Physiology, Tokyo Metropolitan Institute of Medical Science, Japan.
Terasawa
H
H
Ichikawa
S
S
Ogura
K
K
Hatanaka
H
H
Mandiyan
V
V
Ullrich
A
A
Schlessinger
J
J
Inagaki
F
F
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D001665:Binding Sites; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D011522:Protons; D017386:Sequence Homology, Amino Acid
D048868:Adaptor Proteins, Signal Transducing; D000577:Amides; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008024:Ligands; D011506:Proteins; D011522:Protons