Assistant Professor, Molecular Physiology and Biological Physics
- SB, Biology, Massachusetts Institute of Technology
- PhD, Molecular Biophysics and Biochemistry, Yale University
Biochemical, biophysical, structural, and cell biological studies of intracellular membrane tethering and fusion
Our lab uses biochemical, biophysical, structural, and cell biological techniques to study the molecular mechanisms underlying intracellular membrane tethering and fusion in eukaryotes.
Research in the lab centers around a six-subunit complex called HOPS (homotypic vacuole fusion and protein sorting). HOPS is needed for fusion of yeast vacuoles (analogous to lysosomes in metazoan cells) and for traffic from the Golgi apparatus and endosomes to the vacuole.
HOPS is an effector for the vacuolar Rab GTPase Ypt7p, that is, it is recruited to membranes by GTP-bound Ypt7p. It also interacts with vacuolar "SNARE" proteins. (SNAREs are thought to directly catalyze membrane fusion through formation of membrane-bridging "trans-SNARE complexes".) Clearly, HOPS is a central regulator of membrane tethering and fusion, but the biochemical mechanisms by which it functions are still unknown.
Our lab has three main areas of interest:
1. Biochemical and biophysical studies of reconstituted membrane tethering and fusion reactions:
a. What intermolecular interactions mediate membrane tethering?
b. How does the HOPS complex regulate SNARE complex assembly?
c. How does the HOPS complex regulate the activity of SNARE complexes for membrane fusion?
2. Structural studies of HOPS and its interactions with Rab GTPases, SNAREs, and membranes, using X-ray crystallography and scattering techniques, as well as single-particle cryo-electron microscopy.
3. Drug discovery. HOPS is required for Ebola virus infection. HOPS also is required for autophagy, a cellular stress response that plays a role in cancer, protein folding disorders like Alzheimer's disease, and ischemia-reperfusion injury. We are performing high-throughput screening against our lab's in vitro HOPS assay and testing HOPS inhibitors in models for Ebola virus entry and tumor viability.