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

Kemisk Institut

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.

Originalsprog	Engelsk
Tidsskrift	Science (New York, N.Y.)
Vol/bind	345
Udgave nummer	6192
Sider (fra-til)	50-54
Antal sider	5
ISSN	0036-8075
DOI	https://doi.org/10.1126/science.1250373
Status	Udgivet - 2014

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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.), bind 345, nr. 6192, s. 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.}",

note = "Copyright {\textcopyright} 2014, American Association for the Advancement of Science.",

year = "2014",

doi = "10.1126/science.1250373",

language = "English",

volume = "345",

pages = "50--54",

journal = "Science (New York, N.Y.)",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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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.

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 (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6192

ER -

Ras activation by SOS: allosteric regulation by altered fluctuation dynamics

Abstract

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