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

doi:10.1126/science.1250373

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

Department of Chemistry

74 Citations (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.

Original language	English
Journal	Science (New York, N.Y.)
Volume	345
Issue number	6192
Pages (from-to)	50-54
Number of pages	5
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.1250373
Publication status	Published - 2014

Keywords

Allosteric Regulation
Catalytic Domain
Crystallography, X-Ray
Enzyme Activation
Humans
Kinetics
Nucleotides
Protein Interaction Domains and Motifs
Proto-Oncogene Proteins p21(ras)
Son of Sevenless Protein, Drosophila

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Iversen, L., Tu, H-L., Lin, W-C., Christensen, S. M., Abel, S. M., Iwig, J., Wu, H-J., Gureasko, J., Rhodes, C., Petit, R. S., Hansen, S. D., Thill, P., Yu, C-H., Stamou, D., Chakraborty, A. K., Kuriyan, J., & Groves, J. T. (2014). Ras activation by SOS: allosteric regulation by altered fluctuation dynamics. Science (New York, N.Y.), 345(6192), 50-54. https://doi.org/10.1126/science.1250373

Iversen, L, Tu, H-L, Lin, W-C, Christensen, SM, Abel, SM, Iwig, J, Wu, H-J, Gureasko, J, Rhodes, C, Petit, RS, Hansen, SD, Thill, P, Yu, C-H, Stamou, D, Chakraborty, AK, Kuriyan, J & Groves, JT 2014, 'Ras activation by SOS: allosteric regulation by altered fluctuation dynamics', Science (New York, N.Y.), vol. 345, no. 6192, pp. 50-54. https://doi.org/10.1126/science.1250373

@article{41801f7fdabf44bfb5aa42facedd7439,

title = "Ras activation by SOS: allosteric regulation by altered fluctuation dynamics",

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.",

keywords = "Allosteric Regulation, Catalytic Domain, Crystallography, X-Ray, Enzyme Activation, Humans, Kinetics, Nucleotides, Protein Interaction Domains and Motifs, Proto-Oncogene Proteins p21(ras), Son of Sevenless Protein, Drosophila",

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

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year = "2014",

doi = "10.1126/science.1250373",

language = "English",

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pages = "50--54",

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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.

KW - Allosteric Regulation

KW - Catalytic Domain

KW - Crystallography, X-Ray

KW - Enzyme Activation

KW - Humans

KW - Kinetics

KW - Nucleotides

KW - Protein Interaction Domains and Motifs

KW - Proto-Oncogene Proteins p21(ras)

KW - Son of Sevenless Protein, Drosophila

U2 - 10.1126/science.1250373

DO - 10.1126/science.1250373

M3 - Journal article

C2 - 24994643

SN - 0036-8075

VL - 345

SP - 50

EP - 54

JO - Science

JF - Science

IS - 6192

ER -

Ras activation by SOS: allosteric regulation by altered fluctuation dynamics

Abstract

Keywords

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