The Section on Intracellular Protein Trafficking investigates the molecular mechanisms that determine the sorting of integral membrane proteins in the endosomal-lysosomal system. Sorting processes such as rapid internalization from the plasma membrane, targeting to lysosomes and delivery to the basolateral plasma membrane of polarized epithelial cells are all mediated by interactions between signals in the cytosolic domains of integral membrane proteins and adaptor complexes associated with the cytosolic face of membranes. We have been particularly interested in a type of sorting signal referred to as """"""""tyrosine-based"""""""". These signals are recognized by the medium (mu) subunits of four adaptor complexes named AP-1, AP-2, AP-3 and AP-4. This past year, we have conducted studies to determine the cellular functions of these complexes. A form of the AP-1 complex containing a novel subunit named mu1B was found to mediate sorting of integral membrane proteins to the basolateral plasma membrane domain of polarized epithelial cells. The AP-3 complex, on the other hand, was found to be involved in the biogenesis of pigment granules in Drosophila. This observation led us to hypothesize that pigmentation disorders in humans could be similarly caused by abnormal expression or function of the AP-3 complex. In collaboration with William Gahl (Heritable Disorders Branch, NICHD), we identified mutations in the beta3A subunit of AP-3 in two brothers with Hermansky-Pudlak syndrome (HPS), a human disease characterized by reduced pigmentation of the eyes and skin, and blood platelet dysfunction. This constitutes the first human disease shown to be caused by mutations in a component of the signal-recognition machinery. The symptomatology of HPS supports the notion that AP-3 is involved in the biogenesis of lysosome- related organelles such as melanosomes and platelet dense granules in mammals. We are currently investigating the function of AP-4. Finally, we have described a novel family of adaptor-related proteins termed GGAs that appear to be components of protein coats associated with the Golgi complex and involved in protein sorting to lysosomes.
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