Biogenesis of pigment and neuronal cell-specific organelles

Emory University, Atlanta GA

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Abstract

Neural crest-derived cells assemble cell type specific organelles. Melanocytes build pigment granules (melanosomes) required to absorb light in skin and retina. Neurons assemble synaptic vesicles, organelles specialized in the storage and release of neurotransmitters. The mechanisms by which these organelles are formed have started to being unraveled by the identification of mutants that affect both melanosomes and synaptic vesicles. PC12 synaptic vesicles are assembled by a mechanism based on the adaptor complex AP-3, the GTPase ARF-1 and a regulatory kinase that is associated with the adaptor AP-3. Mutations in this membrane trafficking pathway in humans (Hermansky Pudlack II syndrome), mouse and flies are characterized by trafficking defects to melanosomes and synaptic vesicles. Behavioral and pigment dilution phenotypes in AP-3-deficient organisms firmly establish the relevance of this vesiculation mechanism to the physiology of the nervous system and skin. A central question about the mechanisms of organelle biogenesis by adaptors is how the adapt function is regulated and restricted in defined subcellular domains. AKAPs, a family of signaling scaffolds molecules, determine specific interactions between substrates and regulatory enzymes in a spatially restricted way. Their scaffolding function is achieved by holding enzymes and substrates in defined cytoskeletal domains. In this project we propose the hypothesis that adaptor complexes, in particular AP-3, act as scaffolds by its ability to bind kinases, substrates, and the cytoskeleton. This hypothesis is founded fin promising biochemical results that establish the interaction of the AP-3 complex with both an AP-3 specific kinase and the intermediate filament protein peripherin. The completion of this project will further our understanding of the fundamental process of membrane protein sorting. In particular our results will help to illuminate the pathogenesis of genetic diseases that affect skin, eye and nervous system.