IDENTIFICATION OF REGIONS OF THE WISKOTT-ALDRICH SYNDROME PROTEIN RESPONSIBLE FOR ASSOCIATION WITH SELECTED SRC HOMOLOGY-3 DOMAINS

Src homology 3 (SH3) domains have been shown to mediate selected inter actions between signaling molecules and are essential for the activati on of a number of receptor-driven pathways. The Wiskott-Aldrich syndro me protein was identified as a protein that associated selectively wit h the SH3 domains derived from c-Src, p85 alpha, phospholipase C gamma 1, and c-Fgr. Significantly reduced association was detected to the N -terminal SH3 domain and the tandem SH3 domains of p47(phox), and no b inding was detected to the SH3 domain of n-Src, the C-terminal SH3 dom ain of p47(phox), or either of the SH3 domains of p67(phox). Three pep tides corresponding to potential Wiskott-Aldrich syndrome protein SH3 domain binding moths were found to inhibit its association with c-Src, Fgr, and phospholipase C gamma 1 SH3 domains, but not the p85 alpha S H3 domain. These peptides have the sequences MRRQEPLPPPPPPSRG, TGRSGPL PPPPPGA, and KGRSGPLPPVPLGI and show homology with other SH3 domain bi nding motifs. It is possible that the intracellular association of Wis kott-Aldrich syndrome protein with other signaling proteins is mediate d by its SH3 domain-binding regions, and this may play a role in its p utative function as a regulatory molecule in immune cells.