FC0017
Proline rich peptides RLP1  -  Src homology 3 (SH3) domain of phosphatidylinositol 3-kinase (PI3K)

Biological function
Src homology 3 (SH3) domains are integral parts of various signaling proteins. They are capable to bind versatile substrates (e.g. from Abl, dynamin) and even one partner can have a tandem of SH3 binding motif.

Domain organization/sequence features
The common feature is that all the ligands are proline-rich and contain a PPxP motif.

Structural evidence
In case of PI3K SH3 and RLP ligand NMR structure the only residues 3-7 are well-defined and adopt a PPII helix. Two prolines (4,7) directly contact the receptor, others promote formation of the PPII helix. Residues R1 and R6 establish salt bridges.

Biochemical evidence
Mutagenesis showed that residues 1,6 also influence binding affinity likely via electrostatic interactions. Residues flanking the consensus motif also contribute to ligand binding affinity/specificity. The binding affinity is in μM range, which varies by 20 fold upon mutating the flanking residues.

Mechanism category
tethering

Significance
Fuzzy flanking regions contribute to affinity/specificity of binding.