Structural basis of Nuclear Factor 1-X DNA recognition provides prototypic insight into the NFI family

Michele Tiberi, Michela Lapi, Louise Jane Gourlay, Antonio Chaves-Sanjuan, Maurizio Polentarutti, Nicola Demitri, Miriam Cavinato, Diane Marie Valérie Bonnet, Valentina Taglietti, Anna Righetti, Rachele Sala, Silvia Cauteruccio, Amit Kumawat, Rosaria Russo, Alberto Giuseppe Barbiroli, Nerina Gnesutta, Carlo Camilloni, Martino Bolognesi, Graziella Messina () and Marco Nardini ()
Additional contact information
Michele Tiberi: Università degli Studi di Milano, Department of Biosciences
Michela Lapi: Università degli Studi di Milano, Department of Biosciences
Louise Jane Gourlay: Università degli Studi di Milano, Department of Biosciences
Antonio Chaves-Sanjuan: Università degli Studi di Milano, Department of Biosciences
Maurizio Polentarutti: Area Science Park, Elettra Sincrotrone Trieste S.C.p.A
Nicola Demitri: Area Science Park, Elettra Sincrotrone Trieste S.C.p.A
Miriam Cavinato: Università degli Studi di Milano, Department of Biosciences
Diane Marie Valérie Bonnet: Università degli Studi di Milano, Department of Biosciences
Valentina Taglietti: Università degli Studi di Milano, Department of Biosciences
Anna Righetti: Università degli Studi di Milano, Department of Biosciences
Rachele Sala: Università degli Studi di Milano, Department of Biosciences
Silvia Cauteruccio: Università degli Studi di Milano, Department of Chemistry
Amit Kumawat: Università degli Studi di Milano, Department of Biosciences
Rosaria Russo: Università degli Studi di Milano, Department of Pathophysiology and Transplantation
Alberto Giuseppe Barbiroli: Università degli Studi di Milano, Department of Food Environmental and Nutritional Sciences (DeFENS)
Nerina Gnesutta: Università degli Studi di Milano, Department of Biosciences
Carlo Camilloni: Università degli Studi di Milano, Department of Biosciences
Martino Bolognesi: Università degli Studi di Milano, Department of Biosciences
Graziella Messina: Università degli Studi di Milano, Department of Biosciences
Marco Nardini: Università degli Studi di Milano, Department of Biosciences

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Nuclear Factor I (NFI) proteins are involved in adenovirus DNA replication and regulate gene transcription, stem cell proliferation, and differentiation. They play key roles in development, cancer, and congenital disorders. Within the NFI family, NFI-X is critical for neural stem cell biology, hematopoiesis, muscle development, muscular dystrophies, and oncogenesis. Here, we present the structural characterization of the NFI transcription factor NFI-X, both alone and bound to its consensus palindromic DNA site. Our analyses reveal a MH1-like fold within NFI-X DNA-binding domain (DBD) and identify crucial structural determinants for activity, such as a Zn²⁺ binding site, dimeric assembly, and DNA-binding specificity. Given the ~85% sequence identity within the NFI DBDs, our structural data are prototypic for the entire family, a NFI Rosetta Stone that allows decoding a wealth of biochemical and functional data and provides a precise target for drug design in a wider disease context.

Date: 2025
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DOI: 10.1038/s41467-025-65186-0

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