We are investigating how membranes can act as allosteric activators of proteins that pay them visits.
Regulatory enzymes that control metabolism are multi-domain structures whose catalytic sites are often suppressed by inter-domain interactions until some cellular signal binds and disrupts that inhibitory interaction. Many metabolic enzymes and signal-transducing proteins are regulated by membrane binding, which triggers an ON switch. One of these is CTP: phosphocholine cytidylyltransferase (CCT), which catalyzes a key regulatory step in phosphatidylcholine synthesis. Membrane binding and activation of CCT is promoted by increases in minor lipid species such as fatty acids and diacylglycerol, and by dephosphorylation of CCT. The conformational changes in the enzyme associated with its activation are being probed by X-ray diffraction, fluorescence spectroscopy, circular dichroism, mass spec, and molecular dynamics simulations.
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- Ramezanpour, M., Lee, J., Taneva, S., Tieleman, D.P., Cornell, R.B. (2018) An auto-inhibitory helix in CTP:phosphocholine cytidylyltransferase hijacks the catalytic residue and constrains a pliable, domain-bridging helix pair. J. Biol. Chem. 293: 7070-7084.
- Cornell, R.B. and Antonny, B. (2018) CCTalpha Commands Phospholipid Homeostasis from the Nucleus. Devel. Cell 45:419-420
- Cornell, R. B. Membrane lipid compositional sensing by the inducible amphipathic helix of CCT. Biochim. Biophys. Acta, 2016
- Cornell, R.B. and Ridgway, N.D. (2015) CTP: phosphocholine cytidylyltransferase: Function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis. Prog. Lipid Res. 59: 147-171.
- Lee, J., Taneva, S.G., Holland, B., Tieleman, D.P., and Cornell, R.B. Structural basis for auto-inhibition of CTP: phosphocholine cytidylyltransferase (CCT), the regulatory enzyme in phosphatidylcholine synthesis. J. Biol. Chem. 2014