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Introduction

Structure

Grb2 is a small protein of 217 residues with a molecular size of about 25 Da and composed of three remarkable domains : a single SH2 (Src Homology 2) domain (60 to 152 pdb) flanked by two conserved SH3 domains (respectively 1 to 58 and 156 to 215 pdb). It has no catalytic domain. The central SH2 domain binds growth factor receptors (EGFR or PDGFR) or scaffold proteins. It interacts preferentially with a tyrosine phosphorylated sequence with the following motif: pY-X-N-X (X is a hydrophobic residue). The two SH3 domains enable the interaction with the Sos protein (guanine nucleotide exchange factor). The N-Terminal SH3 domain plays the main role in this interaction, it binds a proline-rich region, with the motif PxxP, of the Ct domain of Sos. The Ct SH3 domain improves the overall stability of the Grb2-Sos complex. Moreover, this Ct domain specifically binds to proteins with a P-X-I/L/V-D/N-R-X-X-K-P motif such as Gab1.

N-Terminal SH3 domains of Grb2

encompasse two three-stranded antiparallel β-sheets, one strand crosses the two sheets. This confers a barrel-like structure upon the domain. The first sheet contains the 3 following strands: S1 (Glu2-Ala5), S2 (Ile24-Lys26) and S6 (Ile53-Met55). The second sheet contains the strands S3 (Val27-Asn29), S4 (Trp36-Leu41) and S5 (Asp45-Ile48). The structure of this SH3 domain is stabilized by a high number of hydrophobic residues, which form the centre of the protein.

The SH2 domains of Grb2

encompasse 8 beta strands (61 to 64 ; 82 to 87 ; 95 to 101 ; 104 to 109 ; 111 to 112 ; 118 to 119 ; 124 to 125 ; 149 - 150) and 2 alpha helices (67 to 74 and 128 to 134).