Grant: Operating Grant

In order for the cell to function properly, each intracellular compartment must receive the appropriate complement of proteins and lipids. Mislocalization of even a single component results in any number of human disorders. It is, therefore, not surprising that many different factors work in concert at many different steps to ensure that correct transport of the proteins and lipids is achieved. Virtually every transport event is mediated by small vesicle carriers. Contained within these vesicles is part of the information needed for delivery to the correct compartment. Likewise, the target compartment also contains proteins that recognize the vesicle. Finally, soluble components that cycle on and off of the vesicle and the target membrane are also required. It remains unclear how the actions of each component are coordinated to ensure the overall transport process. We have been focusing on understanding the role of a large multisubunit protein complex called TRAPP in transport between the endoplasmic reticulum (ER) and the Golgi. Mutations in TRAPP subunits have been linked to a specific skeletal defect as well as to a form of mental retardation and microcephaly. This complex activates a protein called a GTPase and can bind to ER-derived transport vesicles. Although the complex was originally thought to tether vesicles to Golgi membranes, there are numerous subunits, implying other functions and interactions. Indeed, we have found that the complex interacts with several proteins that are themselves involved in vesicle transport. Using a combination of biochemistry, cell biology and structural biology techniques we will address the function and interactions of this complex. We will also develop assays to measure the trafficking of large molecules such as collagen that are not properly transported in the skeletal defect mentioned above. A detailed understanding of the organization and interactions of TRAPP will shed light on its function in health and disease.