Specificity landscapes unmask submaximal binding site preferences of transcription factors

Devesh Bhimsaria, José A. Rodríguez-Martínez, Junkun Pan, Daniel Roston, Elif Nihal Korkmaz, Qiang Cui, Parameswaran Ramanathan, Aseem Z. Ansari
2018 Proceedings of the National Academy of Sciences of the United States of America  
We have developed Differential Specificity and Energy Landscape (DiSEL) analysis to comprehensively compare DNA–protein interactomes (DPIs) obtained by high-throughput experimental platforms and cutting edge computational methods. While high-affinity DNA binding sites are identified by most methods, DiSEL uncovered nuanced sequence preferences displayed by homologous transcription factors. Pairwise analysis of 726 DPIs uncovered homolog-specific differences at moderate- to low-affinity binding
more » ... ites (submaximal sites). DiSEL analysis of variants of 41 transcription factors revealed that many disease-causing mutations result in allele-specific changes in binding site preferences. We focused on a set of highly homologous factors that have different biological roles but "read" DNA using identical amino acid side chains. Rather than direct readout, our results indicate that DNA noncontacting side chains allosterically contribute to sculpt distinct sequence preferences among closely related members of transcription factor families.
doi:10.1073/pnas.1811431115 fatcat:gubbnu5bybhpxdfcswcxerexz4