Structural Cell Biology of transport vesicle and organelle biogenesis.

The identity and function of cellular membranes are largely defined by their transmembrane protein composition. Transmembrane protein cargo of an enormous variety of functions is moved between the cell's organelles and its limiting membrane in coated transport vesicles of which clathrin-coated and COPI-coated vesicles are the most common. Coated vesicle formation requires the complex interplay of many cytoplasmic proteins, the membrane itself and the many types of transmembrane protein cargo th at need to be selected for inclusion into a vesicle. When the cell wants to degrade transmembrane or an extracellular proteins, they are delivered to a late endosome, which subsequently fuses with the cell's degradative enzyme store, the lysosome. The HOPS, AP3 and retromer complexes, VARP and many of their binding partners are important players in the critical processes that produce a fully functional late endosomes and lysosomes. We will use an integrated combination of structural studies ( X-ray crystallography and electron microscopy) combined with in vitro and in vivo studies to try and understand how general cargo and SNAREs are selected for incorporation into clathrin, COPI and retromer-coated vesicles and also how the formation and fusion with target membranes of late endosomes, lysosomes and secretory lysosomes are controlled.