TY - JOUR
T1 - Ras activation by SOS
T2 - Allosteric regulation by altered fluctuation dynamics
AU - Iversen, Lars
AU - Tu, Hsiung Lin
AU - Lin, Wan Chen
AU - Christensen, Sune M.
AU - Abel, Steven M.
AU - Iwig, Jeff
AU - Wu, Hung Jen
AU - Gureasko, Jodi
AU - Rhodes, Christopher
AU - Petit, Rebecca S.
AU - Hansen, Scott D.
AU - Thill, Peter
AU - Yu, Cheng Han
AU - Stamou, Dimitrios
AU - Chakraborty, Arup K.
AU - Kuriyan, John
AU - Groves, Jay T.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84903699445&partnerID=8YFLogxK
U2 - 10.1126/science.1250373
DO - 10.1126/science.1250373
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C2 - 24994643
AN - SCOPUS:84903699445
SN - 0036-8075
VL - 345
SP - 50
EP - 54
JO - Science
JF - Science
IS - 6192
ER -