Rizo lab
Our current efforts in this field focus on three exciting areas: 1. Testing the paradigm-shifting model that SNAREs induce membrane fusion acting as local detergents, a principle that may also underlie all types of membrane fusion; 2. Testing another transformative model postulating that synaptotagmin-1 acts as a lever to help triggering membrane fusion in microseconds; and 3. Investigating how Munc13-1 and other large proteins that form specialized sites called active zones regulate neurotransmitter release and presynaptic plasticity. We are also investigating how homologues of these proteins control lytic granule exocytosis at immunological synapses to kill cancer cells.
If you want to learn more details about this research, click on these links:
[1] Ma, C., Su, L., Seven, A. B., Xu, Y., and Rizo, J. (2013) Science 339, 421-425.
[2] Liu, X., Seven, A. B., Camacho, M., Esser, V., Xu, J., Trimbuch, T., Quade, B., Su, L., Ma, C., Rosenmund, C., and Rizo, J. (2016) elife 5, e13696.
[3] Rizo, J. (2022) Annu Rev Biophys 51, 377-408.
We investigate how neurotransmitters are released by calcium-evoked synaptic vesicle exocytosis. We use a wide variety of biophysical approaches, including NMR spectroscopy, X-ray crystallography, cryo-EM, molecular dynamics simulations and liposome fusion assays. Collaborations with Thomas Sudhof, Christian Rosenmund and other neurobiologists allow us to correlate our in vitro studies with physiological data. The importance of this research was emphasized by the award of the 2013 Nobel Prize in Physiology or Medicine to Thomas Südhof, James Rothman and Randy Schekman.
Our lab reconstituted synaptic vesicle fusion with the most central components of the neurotransmitter release machinery1, 2, which, together with results from other groups, defined the functions of these components (color coded in the image above and the model on the right)3. The SNARE proteins synaptobrevin (red), SNAP-25 (green) and syntaxin-1 mediate membrane fusion by forming a tight four-helix bundle called SNARE complex via their SNARE motifs. Syntaxin-1 contains an Habc domain (orange) that binds to the SNARE motif (yellow), forming a self-inhibited ‘closed’ conformation. SNARE complex assembly is orchestrated by Munc18-1 (violet) and Munc13-1 (cyan) via a pathway that starts with Munc18-1 bound closed syntaxin-1. Munc18-1 also binds to synaptobrevin, forming a template for SNARE assembly while Munc13-1 opens syntaxin-1 and bridges the two membranes. The resulting SNARE complex binds to complexin (pink) and synaptotagmin-1 (blue), yielding a spring-loaded primed state that prevents premature fusion before calcium influx but is ready for fast neurotransmitter release when calcium binds to synaptotagmin-1.
