PH-DEPENDENT SELF-ASSOCIATION OF THE SRC HOMOLOGY-2 (SH2) DOMAIN OF THE SRC HOMOLOGOUS AND COLLAGEN-LIKE (SHC) PROTEIN

The Src homologous and collagen-like (SHC) protein plays an essential role in signal transduction pathways in that it participates in the ch ain of events that leads to the activation of the protein Ras. The cry stal structure of the SH2 domain of SHC has been determined using the method of multiple isomorphous replacement at a resolution of 2.5 Angs trom. The SH2 domain of SHC is similar in fold to other SH2 domains. T he peptide-binding surfaces resemble that of the SH2 domain of Src in that a deep pocket is formed where the third amino acid C-terminal to the phosphotyrosine can insert. A novel feature of this structure is t he observation of a disulfide bond and an extensive dimer interface be tween two symmetry-related molecules. Solution studies under reducing conditions using analytical centrifugation and PAGE suggest that the S H2 domain of SHC dimerizes in a pH-dependent manner where low pH condi tions (similar to pH 4.5) are conducive to dimer formation. Dimerizati on of SHC may have important biological implications in that it may pr omote the assembly of large heteromultimeric signaling complexes.