On the prediction of DNA-binding preferences of C2H2-ZF domains using structural models: application on human CTCF

Alberto Meseguer; Filip Årman; Oriol Fornes; Ruben Molina-Fernández; Jaume Bonet; Narcis Fernandez-Fuentes; Baldo Oliva

doi:10.1093/nargab/lqaa046

On the prediction of DNA-binding preferences of C2H2-ZF domains using structural models: application on human CTCF

NAR Genom Bioinform. 2020 Jul 1;2(3):lqaa046. doi: 10.1093/nargab/lqaa046. eCollection 2020 Sep.

Authors

Alberto Meseguer¹, Filip Årman¹, Oriol Fornes², Ruben Molina-Fernández¹, Jaume Bonet³, Narcis Fernandez-Fuentes⁴, Baldo Oliva¹

Affiliations

¹ Structural Bioinformatics Lab (GRIB-IMIM), Department of Experimental and Health Science, University Pompeu Fabra, Barcelona, Catalonia 08005, Spain.
² Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
³ Laboratory of Protein Design & Immunoengineering, School of Engineering, Ecole Polytechnique Federale de Lausanne, Lausanne 1015, Vaud, Switzerland.
⁴ Department of Biosciences, U Science Tech, Universitat de Vic-Universitat Central de Catalunya, Vic, Catalonia 08500, Spain.

Abstract

Cis2-His2 zinc finger (C2H2-ZF) proteins are the largest family of transcription factors in human and higher metazoans. To date, the DNA-binding preferences of many members of this family remain unknown. We have developed a computational method to predict their DNA-binding preferences. We have computed theoretical position weight matrices (PWMs) of proteins composed by C2H2-ZF domains, with the only requirement of an input structure. We have predicted more than two-third of a single zinc-finger domain binding site for about 70% variants of Zif268, a classical member of this family. We have successfully matched between 60 and 90% of the binding-site motif of examples of proteins composed by three C2H2-ZF domains in JASPAR, a standard database of PWMs. The tests are used as a proof of the capacity to scan a DNA fragment and find the potential binding sites of transcription-factors formed by C2H2-ZF domains. As an example, we have tested the approach to predict the DNA-binding preferences of the human chromatin binding factor CTCF. We offer a server to model the structure of a zinc-finger protein and predict its PWM.