3 years ago

Two distinct DNA sequences recognized by transcription factors represent enthalpy and entropy optima

Popov, Yin, Taipale, L., A., J., Nilsson, Jolma, Y., Xu, E., Morgunova
Most transcription factors (TFs) are thought to recognize a single optimal sequence, with mutations to this sequence decreasing binding in a multiplicative manner. However, some TFs display epistasis, with multiple substitutions to their optimal site alleviating each others effects. These TFs can bind to two distinct sequences that represent two local optima in the Gibbs free energy of binding ({Delta}G). To determine the molecular mechanism behind this effect, we solved the structures of human HOXB13 and CDX2 proteins bound to their two optimal DNA sequences, CAATAAA and TCGTAAA. Striking differences were observed in the recognition of the distinct part of the sequence. Whereas the CAA trinucleotide was recognized by a network of direct and water-mediated hydrogen bonds, no such interactions were visible in the TCG structures of both TFs, suggesting that the solvent molecules at the interface were disordered. Thermodynamic analyses by isothermal titration calorimetry (ITC) revealed that both sites were bound with similar {Delta}G. However, the interaction with the CAA sequence was driven by change in enthalpy ({Delta}H), whereas the TCG site was bound with similar affinity due to a smaller loss of entropy ({Delta}S). Additional analysis of BARHL2 and MYF5 using ITC confirmed the presence of entropic and enthalpic optima also for these TFs that can recognize two distinct sequences. The common presence of at least two local optima is general to all macromolecular interactions, as {Delta}G depends on two partially independent variables {Delta}H and {Delta}S according to the central equation of thermodynamics, {Delta}G = {Delta}H - T{Delta}S.

Publisher URL: http://biorxiv.org/cgi/content/short/205906v1

DOI: 10.1101/205906

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