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Direct Observation of the Dynamic Process Underlying Allosteric Signal Transmission

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Sven Brüschweiler^†, Paul Schanda^‡^§, Karin Kloiber^†, Bernhard Brutscher^‡, Georg Kontaxis^†, Robert Konrat^† and Martin Tollinger ^†

Department of Computational & Structural Biology, Max F. Perutz Laboratories, Campus Vienna Biocenter 5, A-1030 Vienna, Austria and Institut de Biologie Structurale Jean-Pierre Ebel, CNRS, CEA, UJF, 41 rue Jules Horowitz, F-38027 Grenoble, France

J. Am. Chem. Soc., 2009, 131 (8), pp 3063–3068

DOI: 10.1021/ja809947w

Publication Date (Web): February 9, 2009

martin.tollinger@univie.ac.at, †

Max F. Perutz Laboratories.

, ‡

Institut de Biologie Structurale Jean-Pierre Ebel.

, §

Current address: Physical Chemistry, ETH Zürich, Wolfgang-Pauli Strasse 10, CH-8093 Zürich, Switzerland.

Section:

General Biochemistry

Abstract

Allosteric regulation is an effective mechanism of control in biological processes. In allosteric proteins a signal originating at one site in the molecule is communicated through the protein structure to trigger a specific response at a remote site. Using NMR relaxation dispersion techniques we directly observe the dynamic process through which the KIX domain of CREB binding protein communicates allosteric information between binding sites. KIX mediates cooperativity between pairs of transcription factors through binding to two distinct interaction surfaces in an allosteric manner. We show that binding the activation domain of the mixed lineage leukemia (MLL) transcription factor to KIX induces a redistribution of the relative populations of KIX conformations toward a high-energy state in which the allosterically activated second binding site is already preformed, consistent with the Monod−Wyman−Changeux (WMC) model of allostery. The structural rearrangement process that links the two conformers and by which allosteric information is communicated occurs with a time constant of 3 ms at 27 °C. Our dynamic NMR data reveal that an evolutionarily conserved network of hydrophobic amino acids constitutes the pathway through which information is transmitted.

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This article has been cited by 2 ACS Journal articles (2 most recent appear below).

Atomistic Kinetic Model for Population Shift and Allostery in Biomolecules
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Journal of the American Chemical Society2011 133 (46), 18999-19005
- Atomistic Kinetic Model for Population Shift and Allostery in Biomolecules
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  Journal of the American Chemical Society2011 133 (46), 18999-19005
  Allosteric signaling in biomolecules is a key mechanism for a myriad of cellular processes. We present a general yet compact model for protein allostery at atomic detail to quantitatively explain and predict structural-dynamics properties of allosteric ...
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Selective Characterization of Microsecond Motions in Proteins by NMR Relaxation
D. Flemming Hansen, Haniqiao Feng, Zheng Zhou, Yawen Bai and Lewis E. Kay
Journal of the American Chemical Society2009 131 (44), 16257-16265
- Selective Characterization of Microsecond Motions in Proteins by NMR Relaxation
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  Journal of the American Chemical Society2009 131 (44), 16257-16265
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