The main areas of interest our group focuses on are the following.

1. Membrane traffic. A eukaryotic cell is composed of many different compartments (eg. nucleus, mitochondria, Golgi apparatus, vacuole, endoplasmic reticulum). Each of these organelles is surrounded by a membrane, thus separating the inside of the organelle from the cytoplasm. Furthermore, each compartment contains its own unique protein and lipid composition. Material can be transferred between specific organelles by small vesicles that bud from one compartment and fuse with another compartment. The central question in this aspect of our research is: how is the specificity in vesicle targeting ensured?

2. Protein-protein interactions. With the advent of proteomics and methodologies for high-throughput analysis, protein-protein interaction networks are taking a central role in biology. We are interested in identifying novel protein-protein interactions, particulalry as they relate to membrane traffic, to better understand this process in eukaryotes. To this end we are using biochemical and genetic approaches to focus on various proteins of the secretory pathway in the hopes that novel interactors will provide clues as to the function of these proteins.

These two main research themes are linked by the following projects.

A. ER-to-Golgi traffic and vesicle tethering complexes

Proteins that are destined for secretion are inserted into the endoplasmic reticulum (ER) and from there are transported in small vesicles to the Golgi complex. The proteins then make their way through the Golgi and end up in vesicles that eventually fuse with the plasma membrane. This entire process is referred to as the secretory pathway. Large, multisubunit complexes referred top as "vesicle tethering complexes" have been implicated in the initial stages of vesicle recognition by target membranes. We are interested in how these complexes localize to the correct intracellular compartment, how they function at the molecular level and what they interact with. Our work has thus far focused on the TRAPP (transport protein particle) vesicle tethering complexes that function at the level of the Golgi apparatus. We have shown that TRAPP is composed of seven (TRAPP I) or ten (TRAPP II) subunits, and that TRAPP I is responsible for ER-to-Golgi targeting while TRAPP II acts later in the secretory pathway. What, then, allows these two complexes to function at different stages of the pathway? How do their functions and mechanism of localization compare to other such vesicle tethering complexes? We are taking a multidisciplinary approach to understanding the function and interactions of these complexes using yeast genetics, biochemistry, cell biology, molecular biology and structural biology.

Membrane traffic and SEDL
It has been established that patients with a particular chondrodysplasia (developmental disorder affecting cartilage) called "spondyloepiphyseal dysplasia late onset" (SEDT) have mutations in one of the subunits of TRAPP called Trs20/TRAPPC2. The defect may lie in the inability of cells to move collagen between the ER and the Golgi. The main question we are addressing is: why is this defect only manifesting itself in chondrocytes (cells that are involved in the synthesis of cartilage) and not in all cell types? To this end, we are characterizing membrane transport in mammalian cells and in yeast cells harboring trs20 mutations found in SEDT patients. We are particularly interested in proteins that interact with mammalian TRAPP subunits, and specifically Trs20/TRAPPC2, and pathways that influence the assembly, localization and function of this complex. Another intriguing question that we are tackling is: how do other pathways influence protein secretion?

C. Regulation of Golgi morphology following cytokinesis

The Golgi undergoes profound changes during the cell cycle. Prior to mitosis, the interphase ribbon-like structure of the Golgi is disrupted and the compartment fragments. During mitosis, Golgi proteins are dispersed throughout the cytoplasm. How is the Golgi rebuilt and positioned following cytokinesis? What determines when it should reform its interphase morphology? Understanding this process may eventually lead to identification of targets for several diseases. 

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