title: Dimer formation through domain swapping in the crystal structure of the Grb2-SH2-Ac-pYVNV complex.
abstract: Src homology 2 (SH2) domains are key modules in intracellular signal transduction. They link activated cell surface receptors to downstream targets by binding to phosphotyrosine-containing sequence motifs. The crystal structure of a Grb2-SH2 domain-phosphopeptide complex was determined at 2.4 A resolution. The asymmetric unit contains four polypeptide chains. There is an unexpected domain swap so that individual chains do not adopt a closed SH2 fold. Instead, reorganization of the EF loop leads to an open, nonglobular fold, which associates with an equivalent partner to generate an intertwined dimer. As in previously reported crystal structures of canonical Grb2-SH2 domain-peptide complexes, each of the four hybrid SH2 domains in the two domain-swapped dimers binds the phosphopeptide in a type I beta-turn conformation. This report is the first to describe domain swapping for an SH2 domain. While in vivo evidence of dimerization of Grb2 exists, our SH2 dimer is metastable and a physiological role of this new form of dimer formation remains to be demonstrated.
authors.affiliation: Department of Structural Chemistry, Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. nikolaus.schiering@eu.pnu.com
authors.forename: N
authors.initials: N
authors.lastname: Schiering
authors.forename: E
authors.initials: E
authors.lastname: Casale
authors.forename: P
authors.initials: P
authors.lastname: Caccia
authors.forename: P
authors.initials: P
authors.lastname: Giordano
authors.forename: C
authors.initials: C
authors.lastname: Battistini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D019281:Dimerization; D066246:ErbB Receptors / Q000737:chemistry*; D051380:GRB2 Adaptor Protein; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010748:Phosphopeptides / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry*; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry*; D014364:Tryptophan / Q000737:chemistry; D014867:Water / Q000737:chemistry; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D046911:Macromolecular Substances; D010748:Phosphopeptides; D011506:Proteins; D014867:Water; D014364:Tryptophan; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met