Proline ligand specificity

The sequence X-P-p-X-P is a consensus sequence for SH3 ligands, in which the two proline residues P are invariant, X is usually an aliphatic residue and p is often a Pro residue. The two invariant proline residues are each bound in a hydrophobic pocket of the SH3 domain. Peptide hgands can be bound in the C- N and also in the N- C direction. Like the SH2 domains, there are many different SH3 domains. The different SH3 domains demonstrate differing binding preferences for Pro-rich sequences, the specificity being determined by the neighboring residues of the invariant proline. 

Fig. 11.17 The dual function of pseudoprolines is demonstrated for the example of proline-rich peptides as ligands for Src homology domains (SH3). Wro building blocks induce the relevant PPM conformation of the ligand and allow in addition the modulation of affinity and specificity by tuning van der Waals contacts and hydrogen bonding interactions of the substituents Rat C2 of YPro to the receptor molecule [195].

In summary, the presence of three acidic residues in the RT loop allows for the formation of a lysine-specific interaction that is unique to c-Crk and its close relatives, explaining the selectivity of this domain. Arginine can form two or three hydrogen bonds with only one or two acidic residues in the RT loop. This is not true for lysine, which needs three carboxylate groups to fuUy satisfy its hydrogen-bonding potential. As shown in Table II, aU interactions typical of the c-Crk-N-SH3 domain are characterized by the presence of lysine downstream from the conserved proline-rich core. Thus, it appears that this domain selects class II ligands. 

Feng, S., Kasahara, C., Rickies, R. J., and Schreiber, S. L. (1995). Specific interactions outside the proline-rich core of two classes of Src homology 3 ligands. Proc. Natl. Acad. Sci. USA 92, 12408-12415. 

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