Grant: $485,528 - National Institutes of Health - Sep. 21, 2009
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Award Description: 'The roles of the V-ATPase at the molecular and physiological level will be investigated. The V0 sector subunit 'a has been shown to play important roles in diverse membrane fusion or secretion functions independent of the V-ATPase proton-pumping activity. These roles include vacuolar fusion, synaptic vesicle exocytosis of neurons, exocytosis in apical secretion of exosomes and morphogens, exocytosis of insulin secretion from pancreatic islets and phagosomal fusion in microglial-mediated neuronal degradation. The molecular mechanism and regulation of all these secretion/membrane fusion events are largely unknown. The neuronal subunit a1 (V100 in fly) is required for SNARE-mediated synaptic vesicle exocytosis. Our preliminary biochemical, structural and in vivo studies have revealed the following: V100 is a target of Ca2+•calmodulin (Ca2+•CaM). In vivo studies in Drosophila demonstrate the physiological significance of this interaction. CaM-binding deficient V100 fails to recruit CaM to synapses and is unable to rescue neuronal function during larval stages, but does not affect V100 protein stability, synaptic localization or neuronal development. V100 can form a ternary ‘core’ complex with target- (or t-) SNARE components, SNAP25 and syntaxin. Ca2+•CaM and t-SNAREs bind to distinct sites on the N-terminal cytosolic region of V100. These findings serve as the framework of the overall goal to investigate the roles of the neuronal subunit a1 of V-ATPase V0 in membrane fusion at the molecular and physiological levels and motivate the following three specific aims: Aim 1: To determine the structure-function relationships of subunits a1. Aim 2: To investigate the binding properties of CaM to subunit a1. Aim 3: To characterize in vivo the CaM- and SNARE-dependent functions of V0 subunit a1 (V100) at Drosophila synapses. '
Project Description: As defined in the Award Description field
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Project Status: Not Started
This award's data was last updated on Sep. 21, 2009. Help expand these official descriptions using the wiki below.