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Ras activation by SOS: Allosteric regulation by altered fluctuation dynamics

机译：通过SOS激活Ras：通过改变波动动态来进行变构调节

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摘要

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.
机译：交换因子Son of Sevenless（SOS）激活小鸟苷三磷酸酶H-Ras是信号转导的重要枢纽。通过蛋白质和膜的相互作用，多层调节可控制SOS的活性。我们表征了单个SOS分子在H-Ras中催化核苷酸交换的比活性。单分子动力学轨迹表明，SOS通过不同的长寿命（超过100秒）功能状态之间的随机波动来采样周转率的广泛分布。 Ras-鸟苷三磷酸（GTP）对SOS的预期变构活化在平均发生率方面明显不足。但是，由Ras-GTP调节进入高活性状态的波动。这揭示了一种机制，其中功能输出可以通过少量酶采样的速率的动态谱而不是整体平均值来确定。

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  • 来源
    《Science》 |2014年第6192期|50-54|共5页
  • 作者

    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;

  • 作者单位

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA,Department of Chemistry, University of Copenhagen, Copenhagen, Denmark;

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA;

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA;

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA, Department of Chemistry, University of Copenhagen, Copenhagen, Denmark;

    Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA, Department of Chemical and Biomolecular Engineering, University of Tennessee, Knoxville, TN 37996, USA;

    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA;

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA, Department of Chemical Engineering, Texas A&M University, College Station, TX 77843, USA;

    Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA, Epizyme, 400 Technology Square, Cambridge, MA 02139, USA;

    Department of Mechanical Engineering, University of California, Berkeley, Berkeley, CA 94720, USA;

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA;

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA;

    Department of Chemistry, MIT, Cambridge, MA 02139, USA;

    Mechanobiology Institute, National University of Singapore, Singapore, Department of Anatomy, The University of Hong Kong, Hong Kong;

    Department of Chemistry and Nano-Science Center, University of Copenhagen, Copenhagen, Denmark;

    Department of Chemical Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA, Department of Chemistry, MIT, Cambridge, MA 02139, USA, Department of Biological Engineering, MIT, Cambridge, MA 02139, USA, Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Cambridge, MA 02139, USA, Institute for Medical Engineering and Science, MIT, Cambridge, MA 02139, USA;

    Howard Hughes Medical Institute, Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA, Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA, Physical Biosciences and Materials Sciences Divisions, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;

    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;

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