Research
My
group focuses on two related problems in cell biology. First, we are
working to understand the fundamental mechansims by which eukaryotic
cell membranes dock and fuse, with a focus on lysosomes, the terminal
organelles in the endosomal system. Small GTPases of the Rab family are
of particular interest. Over sixty Rabs are found in mammalian cells,
and about adozen are present in yeast. These molecular switches exert
control over many membrane trasport processes, but the signals that
cause them to switch between GTP-bound (on) and GDP-bound (off) states
remain poorly understood. We also study the assembly states and
molecular interactions of SNARE proteins. A major goal is to understand
how these proteins function in their native contexts: intact organelle
membranes. We rely on a combination of in vitro reconstitution,
site-directed mutagenesis, protein chemistry, quantitative microscopy,
and materials science.
In
a second, related line of research, we study how cells maintain
membrane integrity during crisis conditions such as mechanical shear,
osmotic shock, or attack by hydrolases. Because membrane repair
requires components of the fusion machinery, fusion and repair probably
occur through shared mechanisms. We initially work with budding yeast,
because it offers an unequalled combination of genetics and
biochemistry, and because the components mediating membrane docking and
fusion are evolutionarily conserved among eukaryotes. Genetic, genomic,
and proteomic tools will be developed for systematic analyses of
membrane integrity and repair.
Selected
Publications
Fratti
RA, Merz AJ, and Wickner WT. Phosphoinositide enrichment at the vertex
ring domain of yeast vacuoles is required for functional SNARE
distribution and membrane fusion. Submitted.
Merz
AJ and Wickner WT. 2004. Resolution of organelle docking and fusion
kinetics in a cell-free assay. Proceedings of the National Academy of
Sciences 101:11549-11553.
Thorngren
N, Collins KM, Fratti R, Wickner WT, and Merz AJ. 2004. A soluble SNARE
drives rapid docking, bypassing the need for ATP and Sec17/18p for
vacuole fusion. In press, EMBO Journal 23:2765-2776.
Merz
AJ and Wickner WT. 2004. Trans-SNARE interactions elicit Ca2+ efflux
from the yeast vacuole lumen. Journal of Cell Biology 164:195-206.
Wang
L, Merz AJ, Collins KM, and Wickner WT. 2003. Hierarchy of protein
assembly at the vertex ring domain for yeast vacuole docking and
fusion. Journal of Cell Biology 160:365-74.
Wang
L, Seeley, S, Wickner WT, and Merz AJ. 2002. Vacuole fusion at a ring
of vertex docking sites leaves membrane fragments within the organelle.
Cell 108:357-69.ww
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