Promiscuous Binding Nature of Sh3 Domains to their Target Proteins

Abstract

SH3 domains are small but important domains in cell-signaling and function through protein-protein interactions. Their promiscuous nature in binding to polyproline peptides makes them much more important because many SH3 domains from different proteins bind to different proteins having polyproline template on their surface. Very subtle changes in the sequence of SH3 domains and the binding peptides determine the specificity of the peptide binding. Recent observation that SH3 domains bind to non- proline peptides makes the scenario of peptide binding involving SH3 domains complicated. If domain swapped dimerization as observed in Eps8-SH3 domain also binds different peptides, it proves the versatility of the SH3 domains in binding to peptides in various ways. An overview of the promiscuity of SH3 domains has been discussed.

VimA is part of the maturation pathway for the major gingipains of Porphyromonas gingivalis W83

“…Several protein domains have been described in both eukaryotic and prokaryotic systems that are involved in protein-protein interactions in these complexes (Pawson et al, 2002;Ponting, 1997;Sheng & Sala, 2001;Agrawal & Kishan, 2002).…”

Rasputin, more promiscuous than ever: a review of G3BP

“…If all family members do function as RasGAP effectors in vivo they may mediate similar, opposing or completely different effects. SH3 domains are relatively promiscuous and subtle differences in the domains and their ligands can alter binding specificity (Agrawal and Kishan, 2002). The contextual differences between the PxxP motifs in the G3BPs could therefore be functionally relevant.…”

“…In vitro binding assays with G3BP1 and G3BP2 suggested that the NTF2-like domain of these proteins was responsible for RasGAP binding (Kennedy et al, 2001). It is rare, but not unprecedented, for non-proline motifs to bind SH3 domains (Agrawal and Kishan, 2002).…”

Structural, Functional, and Bioinformatic Studies Demonstrate the Crucial Role of an Extended Peptide Binding Site for the SH3 Domain of Yeast Abp1p

“…SH3 domains often bind peptides with modest affinities (5-100 M (5)), and many SH3 domains appear to possess low specificity, binding to various PXXP-containing peptides with similar affinities (6 -10). These observations have led to the establishment of a "promiscuous model," which postulates that the signaling specificity of pathways depends primarily on factors other than the intrinsic binding properties of isolated SH3 domains (11), and that short peptide targets are likely sufficient for SH3 domain function. Arguing against this model, it has been shown that some SH3 domains require an extended target peptide (12-30 residues) to achieve maximal binding affinity (12)(13)(14)(15).…”