Ras activation by SOS: allosteric regulation by altered fluctuation dynamics

Lars Iversen, Hsiung-Lin Tu, Wan-Chen Lin, Sune M. Christensen, Steven M. Abel, Jeff Iwig, Hung-Jen Wu, Jodi Gureasko, Christopher Rhodes, Rebecca S. Petit, Scott D. Hansen, Peter Thill, Cheng-Han Yu, Dimitrios Stamou, Arup K. Chakraborty, John Kuriyan, Jay T. Groves

74 Citationer (Scopus)

Abstract

Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average.

OriginalsprogEngelsk
TidsskriftScience (New York, N.Y.)
Vol/bind345
Udgave nummer6192
Sider (fra-til)50-54
Antal sider5
ISSN0036-8075
DOI
StatusUdgivet - 2014

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