Senior Fellowship research summary

Biochemical reactions within cells are compartmentalized by intracellular membranes into distinct membrane-bound organelles. Each organelle is different, sequestering different sets of competing or incompatible reactions. How do cells solve this problem? Macromolecules - including proteins that make up these organelles have to be sorted among them appropriately. By delivering structural and functional components to their proper place, intracellular sorting mechanisms actually contribute to the formation of the organelles. My laboratory would like to understand how this process works?

The organelles of the endocytic pathway are particularly pleiomorphic and contribute to forming many different classes of physiologically important organelles in different cell types. Among these organelles, melanosomes in melanocytes and others belong to a class of Lysosome-related organelles (LRO) which coexist with lysosomes in their respective cell types. Interestingly, formation and function of several LRO are defective in a multisystem genetic disorder, Hermansky-Pudlak Syndrome (HPS) and it is characterized by oculocutaneous albinism, platelet deficiency and often lung fibrosis. These defects result from mutations in 15 genes in mouse and 8 genes in human which encodes five different multi-subunit protein complexes, includes BLOC (Biogenesis of Lysosome-related Organelles Complex)-1, BLOC-2, BLOC-3, AP (Adaptor Protein)-3, HOPS (Homotypic Vacuolar Protein Sorting) complex and other subunits. My laboratory interested in understanding the molecular mechanism of protein transport steps mediated by these complexes to melanosomes and other organelles.