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BioSoft-Colloquium: "Global Low Frequency Protein Motions Carry Signals: Allosteric Regulation of CRP/FNR family transcription factors"

Prof. Tom McLeish, Durham University

16.12.2013 14:00 Uhr


We present a foundational theory for how allostery can occur as a function of low frequency dynamics without a change in protein structure [1-3]. We have generated coarse-grained models that describe the protein backbone motions of the homodimeric CRP/FNR family transcription factors, Catabolite Activated Protein (CAP) of Escherichia coli and GlxR of Corynebacterium glutamicum [3]. We demonstrate that binding the first molecule of cAMP ligand modulates the global normal modes resulting in negative co-operativity for binding the second cAMP ligand without a change in mean structure. Crucially, the value of the co-operativity is itself controlled by the interactions around a set of third allosteric “control sites” (mapped for CAP in figure 1).  The theory makes key experimental predictions, validated by analysis of variant proteins (mutating the key sites) by a combination of structural biology and isothermal calorimetry. A quantitative description of allostery as a free energy landscape revealed a protein ‘design space’ that identified the key inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, by analyzing naturally occurring CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. Our study therefore reveals significant features of the mechanistic basis for allostery. The methodology establishes the means to engineer allosteric mechanisms that are driven by low frequency dynamics [4].



[1] R.J. Hawkins and T.C.B. McLeish, Phys. Rev. Letts, 2004, 93, 098104

[2] R. J. Hawkins and T. C. B. McLeish, Biophys. J., 2006, 91, 2055-2062

[3] H. Toncrova and T.C.B. McLeish, Biophys. J., 2010 98, 2317-2326

[4] T.L. Rogers et al., PLoS Biol, 2013 to appear.





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