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Molecular kinetics. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics.
Science.Jul 4, 2014;345(6192):50-4.
Iversen L, Tu HL, Lin WC, Christensen SM, Abel SM, Iwig J, Wu HJ, Gureasko J, Rhodes C, Petit RS, Hansen SD, Thill P, Yu CH, Stamou D, Chakraborty AK, Kuriyan J, Groves JT.
Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA. Mechanobiology Institute, National University of Singapore, Singapore. Physical Biosciences and Materials Sciences Divisions, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Berkeley Education Alliance for Research in Singapore, 1 Create Way, CREATE tower level 11, University Town, Singapore 138602. email@example.com.
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.