Molecular mechanisms of vesicular transport and ciliogenesis in eukaryotic cells

My group is interested in understanding the molecular mechanisms of vesicular transport and, lately, ciliogenesis in eukaryotic cells. Vesicular transport is essential for sorting and delivering newly synthesized proteins and lipids from the endoplasmic reticulum (ER) through the Golgi to target compartments including the cilium. Cilia are specialized eukaryotic organelles that are highly conserved from protists to mammals. These organelles consist of the membrane-sheathed axoneme, an extension of the mother centriole, and at least 360 associated proteins. Eukaryotic cilia and flagella have attracted much attention in recent years because of their role in the transduction of extracellular signals and their association with an ever expanding number of human disorders. Such disorders include respiratory distress syndrome, male sterility, polycystic kidney disease, retinal degeneration, and Bardet-Biedl syndrome.

Our goal is to elucidate at the atomic level the assembly mechanisms of the protein complexes for cargo transport to and within the cilium. We mainly use X-ray crystallography to visualize these proteins and their complexes; other biophysical techniques such as dynamic light scattering, differential scanning calorimetry, and analytical ultracentrifugation will as well be employed to study the architecture and assembly of the protein complexes. Large assemblies will also be examined by cryo-electron microscopy. Our structural studies will be complemented by site-directed mutagenesis and in vitro/vivo experiments to test our mechanistic hypotheses. The available new structures will enhance our understanding of how these complexes function and provide hints as to how their malfunction leads to human diseases.