Protein Domains and Signal Transduction

FIG 24.3  The SH3 domain of the Src kinase Fyn complexed with a peptide ligand corresponding to residues 91–104 of the p85 subunit of PI 3-kinase.

The view on the left shows the domain in cartoon format and the peptide as sticks. Three of the aromatic amino acid side chains that define the binding site are also shown as sticks (magenta). The right hand view shows the structure rotated about a vertical axis illustrating the left-handed helical conformation of the ligand (1azg.pdb15).

the target motif N-P-X-pY,12 quite distinct from the sequences recognized by SH2 domains. This is because the binding sites are dissimilar. PTB domains lack binding pockets that bury the target motif, attaching it instead to the side of the -barrel. The phosphate group remains relatively exposed.

A characteristic that some PTB domains share with PH domains is their ability to bind to acidic phospholipid head groups, such those of the phosphoinositides. This enables them to locate at membrane surfaces where they may then encounter their peptide ligands.14

SH3 domains

SH3 (Src homology 3) domains consist of ~60 amino acids arranged to form a compact, twisted -barrel structure. They bind to proline-rich sequences. These generally consist of 8–10 residues and include at least two prolines in a PxxP motif. A typical SH3 domain is depicted in Figure 24.3 together with a peptide ligand. Proline-rich sequences are abundant in multicellular species and seem to have coevolved with SH3 domains (and EVH1 and WW domains to which they can also bind). The utility of these sequences stems from the cyclic structure of proline, which limits the range of conformations that it can adopt. It therefore tends to occur at the ends of, or between, regions of secondary structure, particularly at loops and turns. A short sequence having

more than one proline adopts a stable, left-handed, extended helical structure (three residues per turn) that can tolerate variations in sequence. Such type II polyproline helices commonly occur on the surfaces of proteins.

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