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We are determining how organelles are inherited and how they maintain their identity in both yeast and mammals. Ras-like GTPases (called Rabs) interact in a signal cascade that regulates the flow of membrane traffic. Rabs are molecular switches that are active in their GTP-bound form and inactive when bound to GDP. Using GFP tagged proteins and microscopy, we are visualizing how organelles are formed and transferred from mother to daughter cells. In yeast, we are using mutational analysis to isolate mutants that disrupt these cellular events. This approach has led to the identification of membrane proteins and novel complexes as key players in these processes. In vitro assays are also being used to reconstitute these events at a biochemical level.

The TRAPP complexes are multimeric guanine nucleotide exchange factors (GEF) that activate the GTPase Rab1. A focus of our studies is to understand the role of Rab1, which has been implicated in neurodegenerative diseases such as Parkinson’s. TRAPP requires four subunits (Bet3, Bet5, Trs23 and Trs31) for its GEF activity. How each of these subunits contributes to this activity has recently been defined. The smaller TRAPP complex, TRAPPI, specifically binds to ER-derived vesicles and tethers them to their acceptor compartment. The larger complex, TRAPPII, is a Rab1 GEF that contains adaptor subunits which tether it to an early Golgi compartment. Recently, a TRAPP subunit has been implicated in autophagy, a catabolic process that targets the degradation of proteins and organelles for lysosomal degradation. Understanding the mechanism of autophagy is important for the study of cancer and certain neurological diseases

Key words: protein traffic, peripheral membrane proteins, human disease, organelle inheritance, Rab

Model systems: humans and yeast

Recent Publications:

Cai, Y., Chin, H., Lazarova, D., Menon, S., Fu, C., Cai, H., Sclafani, A., Rodgers, D.W., De La Cruz, E., Ferro-Novick, S. *, and Reinisch, K* (2008). The structural basis for activation of the Rab Ypt1p by the TRAPP membrane tethering complexes. Cell 133, 1202-1213. (*co-corresponding senior authors)

Cai, H., Yu, S., Menon, S., Cai, Y., Lazarova, D., Fu, C., Reinisch, K., Hay, J. C. and Ferro-Novick, S. (2007). TRAPPI tethers COPII vesicles by binding the coat subunit Sec23p. Nature 445, 941-944.

Du, Y., Walker, L., Novick, P. and Ferro-Novick, S. (2006). Ptc1p regulates cortical ER inheritance via Slt2p. EMBO J. 25, 4413-4422.

Track(s):
MCB