Pfeffer Lab. Stanford University. Biochemistry Dept. Copyright © 2012. All Rights Reserved.
We are interested in understanding the molecular basis by which receptors are
transported between membrane compartments in human cells. Rab GTPases
are master regulators of these events: they catalyze transport vesicle formation,
as well as vesicle motility docking and fusion. The human genome encodes ~70
Rabs and we are interested in learning how they localize to different compartments,
how they are regulated, and how they interact with specific effector proteins to
drive membrane traffic.
Current work focuses on transport vesicle tethering at the Golgi mediated by a long,
coiled coil protein called GCC185 (1,2) and a Rho GTPase family member
(RhoBTB3) that is actually an ATPase (3). GCC185 is anchored to membranes by
two molecules of Arl1 GTPase and two molecules of Rab6. With Tim Fenn and
Axel Brunger, we solved the structure of this complex (1). We are working to
understand how GCC185 captures vesicles at the Golgi prior to membrane fusion (2).
We are also studying the Niemann Pick Type C (NPC)1 protein that when mutated,
leads to disease. NPC1 patients suffer the consequences of excess cholesterol
and sphingolipid accumulation in endosomes and lysosomes. We seek to determine
the precise role of NPC1 in cholesterol regulation and have just discovered that
NPC2 binds to NPC1 protein to transfer cholesterol from the lumen of lysosomes to
the limiting membrane of that compartment (4).