Three dimensional structures of SH2 and SH3 domains of the Abl and Shc oncoproteins

Src homology (SH) domains 2 and 3 are noncatalytic domains that are conserved among a series of cytoplasmic signaling proteins regulated by receptor protein kinases and nonreceptor kinases. SH2 and SH3 domains mediate protein-protein interactions by their ability to bind to specific phosphorylated tyrosine residues or proline-rich sequences, respectively. The SH2 and SH3 domains also have been shown to have regulatory functions for the catalytic domains of proteins which contain them. Binding of ligands to these domains can activate or inhibit the catalytic functions of the proteins.;Structure of the Abl SH3-SH2 domains has been determined at a resolution of 2.5 A with an R-factor of 18.3%. The structure shows that the protein exists as a monomer with significant intramolecular contact between the bc loop of the SH3 domain and BC loop of the SH2 domain. In addition, compared to other SH2 structures, the Abl SH3-SH2 structure shows that the BC loop of the SH2 domain is flatter, and the resulting phosphotyrosine pocket is narrow. These results suggest that there are direct interactions between the SH3 and SH2 domains, and that these interactions may affect the ligand binding properties of the SH2 domain. The results are also consistent with biochemical data which showed that the functions of one of the domains are influenced by the other.;Structures of the Abl SH2 domain, and complex of the SH2 domain and phosphotyrosine containing peptide were determined at a resolution of 3.0 A with R-factors of 18.7% and 19.2%, respectively. Overall structures of the liganded and unligated Abl SH2 domains are very close to that of the SH2 part in the Abl SH3-SH2 structure except in the BC loop. Mechanisms for the pTyr binding are similar to those shown in other SH2/peptide complex structures.;Crystal structure of the Shc SH2 domain has been determined at a resolution of 2.2A with an R-factor of 20.8%. Compared to the Abl SH2 domain, the Shc SH2 domain has a relatively longer BG loop, and the BG loop contains two short antiparallel ;Three dimensional structures of SH2 and SH3-SH2 domains of Abl tyrosine kinase, and SH2 domain of Shc protein have been determined by X-ray crystallography. Abl protein is one of a few proteins which are directly involved in human malignancies. Biochemical studies with Abl SH3-SH2 domains showed that relative positions of the two domains are important for their regulatory functions for the catalytic function of the Abl protein. The structure of the Shc SH2 domain which has unique ligand specificities was determined to investigate the structural basis for the specificities.