Dimer formation through domain swapping in the crystal structure of the Grb2-SH2-Ac-pYVNV complex

Src homology 2 (SH2) domains are key modules in intracellular signal transd uction. They link activated cell surface receptors to downstream targets by binding to phosphotyrosine-containing sequence motifs. The crystal structu re of a Grb2-SH2 domain-phosphopeptide complex was determined at 2.4 Angstr om resolution. The asymmetric unit contains four polypeptide chains. There is an unexpected domain swap so that individual chains do not adopt a close d SH2 fold. Instead, reorganization of the EF loop leads to an open, nonglo bular fold, which associates with an equivalent partner to generate an inte rtwined dimer. As in previously reported crystal structures of canonical Gr b2-SH2 domain-peptide complexes, each of the four hybrid SH2 domains in the two domain-swapped dimers binds the phosphopeptide in a type 1 beta -turn conformation. This report is the first to describe domain swapping for an S H2 domain. While in vivo evidence of dimerization of Grb2 exists, our SH2 d imer is metastable and a physiological role of this new form of dimer forma tion remains to be demonstrated.