Department of Biological Sciences, National University of Singapore
INPEC node since 2005
With our unexpected discovery in 2005 that insoluble proteins including the most hydrophobic integral membrane fragment could all be solubilized in pure water, we have been focused on characterizing the conformations, dynamics and membrane-interactions of ALS-causing proteins including MSP, SOD1 and profilin-1 mutants as well as TDP-43 and FUS. The results led to our proposal that aggregation-prone proteins also have strong capacity in attacking membranes, thus representing a general mechanism for “gain of toxicity”. Recently we decoded that ATP, the universal energy currency for all living cells mysteriously with high concentrations (2-12 mM), shares the same mechanism with nucleic acids in biphasically modulating liquid-liquid phase separation (LLPS) by specific binding to Arg residues in intrinsically-disordered regions. In general, in addition to being a biological hydrotrope, ATP can also act as a bivalent binder and a hydration mediator in controlling protein hemostasis, thus owning a previously-unknown category of energy-independent functions at mM.
Keywords: water and salts in protein folding and aggregation; ATP functions at mM; mechanisms for protein-aggregation diseases; intrinsically-disordered proteins and liquid-liquid phase separation (LLPS); protein dynamics in catalysis and small molecule-protein interaction; protein NMR spectroscopy; molecular virology