Proteome-wide solubility and thermal stability profiling reveals distinct regulatory roles for ATP

Sindhuja Sridharan, Nils Kurzawa, Thilo Werner, Ina Günthner, Dominic Helm, Wolfgang Huber, Marcus Bantscheff () and Mikhail M. Savitski ()
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Sindhuja Sridharan: Genome Biology Unit, European Molecular Biology Laboratory
Nils Kurzawa: Genome Biology Unit, European Molecular Biology Laboratory
Thilo Werner: Cellzome, A GSK company
Ina Günthner: Cellzome, A GSK company
Dominic Helm: Proteomics Core Facility, European Molecular Biology Laboratory
Wolfgang Huber: Genome Biology Unit, European Molecular Biology Laboratory
Marcus Bantscheff: Cellzome, A GSK company
Mikhail M. Savitski: Genome Biology Unit, European Molecular Biology Laboratory

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Adenosine triphosphate (ATP) plays fundamental roles in cellular biochemistry and was recently discovered to function as a biological hydrotrope. Here, we use mass spectrometry to interrogate ATP-mediated regulation of protein thermal stability and protein solubility on a proteome-wide scale. Thermal proteome profiling reveals high affinity interactions of ATP as a substrate and as an allosteric modulator that has widespread influence on protein complexes and their stability. Further, we develop a strategy for proteome-wide solubility profiling, and discover ATP-dependent solubilization of at least 25% of the insoluble proteome. ATP increases the solubility of positively charged, intrinsically disordered proteins, and their susceptibility for solubilization varies depending on their localization to different membrane-less organelles. Moreover, a few proteins, exhibit an ATP-dependent decrease in solubility, likely reflecting polymer formation. Our data provides a proteome-wide, quantitative insight into how ATP influences protein structure and solubility across the spectrum of physiologically relevant concentrations.

Date: 2019
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DOI: 10.1038/s41467-019-09107-y

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