Molecular protein-DNA evolution

Jalal et al. elucidate the molecular basis for how specific protein-DNA interactions can evolve, using ParB and Noc as models. Using X-ray crystallography, molecular dynamics simulations and deep mutational scanning, they define protein-DNA interfaces and suggest that permissive mutations must be introduced before specificity-switching mutations to reprogram specificity

Specific interactions between proteins and DNA are essential to many biological processes. Yet, it remains unclear how the diversification in DNA-binding specificity was brought about, and the mutational paths that led to changes in specificity are unknown. Using a pair of evolutionarily related DNA-binding proteins, each with a different DNA preference (ParB [Partitioning Protein B] and Noc [Nucleoid Occlusion Factor], which both play roles in bacterial chromosome maintenance), we show that specificity is encoded by a set of four residues at the protein-DNA interface. Combining X-ray crystallography and deep mutational scanning of the interface, we suggest that permissive mutations must be introduced before specificity-switching mutations to reprogram
specificity and that mutational paths to new specificity do not necessarily involve dual-specificity intermediates. Overall, our results provide insight into the possible evolutionary history of ParB and Noc and, in a broader context, might be useful for understanding the evolution of other classes of DNA-binding proteins.

ASB Jalal, NT Tran, CE Stevenson, EW Chan, RL, Xiao Tan, A Noy, DM Lawson, TBK Le (2020). “Diversification of DNA-binding specificity via permissive and specificity-switching mutations in the ParB/Noc protein family” Cell Reports, 32, 107928. https://doi.org/10.1016/j.celrep.2020.107928

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