Functional relevance of the disulfide-linked complex of the N-terminal PDZdomain of InaD with NorpA

In Drosophila, phototransduction is mediated by G(q)-activation of phosphol ipase C and is a well studied model system for understanding the kinetics o f signal initiation, propagation and termination controlled by G proteins. The proper intracellular targeting and spatial arrangement of most proteins involved in fly phototransduction require the multi-domain scaffolding pro tein InaD, composed almost entirely of five PDZ domains, which independentl y bind various proteins including NorpA, the relevant phospholipase C-beta isozyme. We have determined the crystal structure of the N-terminal PDZ dom ain of InaD bound to a peptide corresponding to the C-terminus of NorpA to 1.8 Angstrom resolution. The structure highlights an intermolecular disulfi de bond necessary for high affinity interaction as determined by both in vi tro and in vivo studies. Since other proteins also possess similar, cystein e-containing consensus sequences for binding PDZ domains, this disulfide-me diated 'dock-and-lock' interaction of PDZ domains with their ligands may be a relatively ubiquitous mode of coordinating signaling pathways.