Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67phox, Grb2 and Pex13p

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Abstract
The basic function of the Src homology 3 (SH3) domain is considered to be binding to proline‐rich sequences containing a PxxP motif. Recently, many SH3 domains, including those from Grb2 and Pex13p, were reported to bind sequences lacking a PxxP motif. We report here that the 22 residue peptide lacking a PxxP motif, derived from p47phox, binds to the C‐terminal SH3 domain from p67phox. We applied the NMR cross‐saturation method to locate the interaction sites for the non‐PxxP peptides on their cognate SH3 domains from p67phox, Grb2 and Pex13p. The binding site of the Grb2 SH3 partially overlapped the conventional PxxP‐binding site, whereas those of p67phox and Pex13p SH3s are located in different surface regions. The non‐PxxP peptide from p47phox binds to the p67phox SH3 more tightly when it extends to the N‐terminus to include a typical PxxP motif, which enabled the structure determination of the complex, to reveal that the non‐PxxP peptide segment interacted with the p67phox SH3 in a compact helix–turn–helix structure (PDB entry 1K4U).