title: Functional relevance of the disulfide-linked complex of the N-terminal PDZ domain of InaD with NorpA.
abstract: In Drosophila, phototransduction is mediated by G(q)-activation of phospholipase C and is a well studied model system for understanding the kinetics of 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 protein InaD, composed almost entirely of five PDZ domains, which independently bind various proteins including NorpA, the relevant phospho lipase C-beta isozyme. We have determined the crystal structure of the N-terminal PDZ domain of InaD bound to a peptide corresponding to the C-terminus of NorpA to 1.8 A resolution. The structure highlights an intermolecular disulfide bond necessary for high affinity interaction as determined by both in vitro and in vivo studies. Since other proteins also possess similar, cysteine-containing consensus sequences for binding PDZ domains, this disulfide-mediated 'dock-and-lock' interaction of PDZ domains with their ligands may be a relatively ubiquitous mode of coordinating signaling pathways.
authors.affiliation: Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Kimple
authors.forename: D P
authors.initials: DP
authors.lastname: Siderovski
authors.forename: J
authors.initials: J
authors.lastname: Sondek
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002461:Cell Line, Transformed; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry*; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D005136:Eye Proteins / Q000737:chemistry* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054799:Phospholipase C beta; D017956:Photoreceptor Cells, Invertebrate / Q000737:chemistry* / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D010738:Type C Phospholipases / Q000737:chemistry* / Q000502:physiology
chemical_list: D004220:Disulfides; D029721:Drosophila Proteins; D005136:Eye Proteins; D010455:Peptides; C091568:inaD protein, Drosophila; D010738:Type C Phospholipases; C468371:NorpA protein, Drosophila; D054799:Phospholipase C beta; D043265:Phosphatidylinositol Diacylglycerol-Lyase