The physiological significance of subcellularly localized G protein signaling is now increasingly appreciated in a number of systems. However, the molecular players and events involved in positioning and regulating the signaling complexes are poorly understood. The long-term objective of the proposed research is aimed at studying the molecular and biochemical mechanisms that govern the assembly and regulation of signaling complexes. The proposed experiments in this application focus on a Drosophila visual protein known as INAD (inactivation no afterpotential D). This protein is essentially composed of five PDZ domains, a class of protein interaction modules that possess diverse substrate specificity and usually bind to short linear peptides of target proteins. Genetic studies have shown that INAD acts as a scaffold to organize the phototransduction complex by interacting with multiple signaling proteins including rhodopsin, G proteins, phospholipases, post-translational enzymes, and ion channels. The fundament questions concerning scaffold proteins are their mechanistic roles both in assembly of the signal complexes and in activation and deactivation of G protein-coupled signal transmission. This project is aimed at understanding the molecular interaction between INAD and two signaling enzymes: phospholipase C (norpA) and protein phosphatases (rdgC). Both proteins are essential for phototransduction by mediating activation (PLC) and deactivation (RDGC, phosphatase). Interestingly, the spatially-localized activities of these two enzymatically as well as functionally distinct enzymes are coupled with INAD through specific protein-protein interactions. Results from the proposed experiments should provide insights into the mechanistic roles of the INAD-signaling enzyme interactions in Drosophila phototransduction. The G-coupled signaling is critical for phototransduction and many other biological processes. Our knowledge of the molecular principles of these interactions is, therefore, essential for the full understanding of their roles in both health and in disease.
| Cheng, Jie; Moyer, Bryan D; Milewski, Michal et al. (2002) A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression. J Biol Chem 277:3520-9 |
