Structure of an SH2 domain of the p85α subunit of phosphatidylinositol-3-OH kinase

New insights into protein‐tyrosine kinase receptor signaling complexes

“…As indicated in Figure 1, two loops in particular, loop BC and loop BG, appear to differ in the complexed conformation (Lck-SH2) compared with the uncomplexed conformation (p85-N-terminal SH2). This is consistent with the observation that these two loops are poorly defined in the two solution structures and are likely to be relatively mobile (Booker et a]., 1992;Overduin et al, 1992). It would appear, therefore, that the role of the SH2 domain is largely one of sequence-specific phosphotyrosine recognition, although it will be necessary to study the structure of SH2 domains within the context of the rest of appropriate proteins before an allosteric mechanism for SH2 domain-mediated signal transduction can be excluded.…”

“…All of these tyrosines lie within the consensus sequence YxxM (where x can be a wide range of possible residues). This motif appears therefore to be important for PI 3-kinase binding (Cantley et al, 1991) and recent structural studies on the N-terminal SH2 domain of p85a provide a molecular basis for this specificity (Booker et al, 1992). Studies with the recombinant N-and C-terminal SH2 domains of p85a have shown that both are capable of binding to sequences containing YxxM motifs.…”

“…Knowledge of SH2 domain function at the molecular level has been greatly enhanced by recent structural studies on several different SH2 domains-including those of Ab1 , Src (Waksman et al, 1992), and Lck (Eck et al, 1993) PTKs-and on the N-terminal SH2 domain of the p85 subunit of the PI 3-kinase (Booker et al, 1992). It is clear from a comparison of the published solution and X-ray structures that the SH2 domain represents a well-conserved protein fold consisting of a central antiparallel / 3 sheet with an a helix packing onto each face of the sheet.…”

“…It is clear from a comparison of the published solution and X-ray structures that the SH2 domain represents a well-conserved protein fold consisting of a central antiparallel / 3 sheet with an a helix packing onto each face of the sheet. Variations in structure between different members of the SH2 domain family are found mainly in the length of the loops joining these secondary structural elements (Booker et al, 1992;Overduin et al, 1992;Waksman et al, 1992Waksman et al, , 1993Eck et al, 1993). A nomenclature for the a helices (aA and aB) and / 3 strands (PA-PG) has been proposed that allows these insertions and deletions to be placed when making comparisons of the different SH2 domain structures ( (blue) and Lck (green) SH2 domains.…”

“…A nomenclature for the a helices (aA and aB) and / 3 strands (PA-PG) has been proposed that allows these insertions and deletions to be placed when making comparisons of the different SH2 domain structures ( (blue) and Lck (green) SH2 domains. The backbone atoms for the SH2 domains from p85a (Booker et al, 1992) and Lck (Eck et al, 1993) are shown superimposed on the coFserved region of the central 6 sheet (root mean square deviation 0.79 A). Also indicated are the a helices and 6 strands following the convention of Eck et al (1993) and the two loops (BC and BG) thought to undergo conformational change upon phosphotyrosine-peptide binding.…”