Project 458989

In Canada, more than 1 in 500 people are affected by Parkinson's and similar movement disorders, such as ataxia. Mutations in the four human versions of vacuolar protein sorting 13 (VPS13) cause distinct neurological disorders, including these movement disorders. The single yeast copy of Vps13 interacts with proteins at different internal cell structures, called organelles. Through these interactions, Vps13 is thought to act like a firehose for fats, transporting them from one organelle to another. This is important as organelles require membranes made of fats to grow, function, and communicate with one another. Defects in these interactions and transport could be why mutations in VPS13 lead to disease. It is thought that this Vps13 firehose must be docked properly before fats can be transported across, like a bridge to cross a river. My work focuses on discovering the protein adaptors that dock Vps13 to different membranes and what parts of both proteins allow for docking. Previously, we had identified three adaptors at different membranes and found that Vps13 is recruited to these adaptors using a Vps13 adaptor-binding (VAB) domain, a feature shared in all human VPS13 homologs. Based on recent evidence, we hypothesize that several more Vps13 adaptors exist. My current focus is on finding these adaptors and determining how they compare to the adaptors already identified. Finally, though all VPS13 homologs have a VAB domain, human VPS13D has a unique feature within its VAB. It is a lectin, a domain known to bind certain sugars on membranes. Since this feature could affect binding, we will also study this lectin and VPS13D in different cell lines to see if it allows for VPS13D to uniquely dock at membranes, distinct from other VPS13 copies. Collectively, this study will determine how the VAB domain works at a molecular level. When it is understood how VPS13 works molecularly, scientists may be able to develop therapeutics to treat the previously mentioned diseases.