An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90
Hw. Shin et al., An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90, J NEUROSC, 20(10), 2000, pp. 3580-3587
Members of the postsynaptic density-95 (PSD-95)/SAP90 family of membrane-as
sociated guanylate kinase (MAGUK) proteins function as multimodular scaffol
ds that organize protein-signaling complexes at neuronal synapses. MAGUK pr
oteins contain PDZ, Src homology 3 (SH3), and guanylate kinase (GK)-like do
mains, all of which can function as sites for specific protein-protein inte
ractions. We report here a direct protein-protein interaction between the S
H3 domain and the GK region in the PSD-95 family of MAGUKs. The SH3 domain
of the PSD-95 family appears to have an atypical binding specificity, becau
se the classical SH3 binding (-P-X-X-P-) motif is absent from the GK domain
. Although SH3-GK binding can occur in either an intramolecular or intermol
ecular manner, the intramolecular mode is preferred, possibly because of ad
ditional tertiary interactions available when the SH3 and GK domains are ad
jacent in the same polypeptide. Mutations disrupting the intramolecular SH3
-GK interaction do not interfere with PSD-95 association with the K+ channe
l Kv1.4 or with the GK domain-binding protein GKAP. The same mutations, how
ever, inhibit the clustering of Kv1.4 by PSD-95, suggesting that the intram
olecular SH3-GK interaction may modulate the clustering activity of PSD-95.