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oai:recercat.cat:2445/1401292025-12-05T12:19:28Zcom_2072_1057col_2072_478916col_2072_478917col_2072_478929

DNA binding induces a nanomechanical switch in the RRM1 domain of TDP-43 Wang, Yong Jian Rico-Lastres, Palma Lezamiz, Ainhoa Mora, Marc Solsona Sancho, Carles Stirnemann, Guillaume Garcia-Manyes, Sergi ADN Química Gens Proteïnes supressores de tumors DNA Chemistry Genes Tumor suppressor protein Understanding the molecular mechanisms governing protein-nucleic acid interactions is fundamental to many nuclear processes. However, how nucleic acid binding affects the conformation and dynamics of the substrate protein remains poorly understood. Here we use a combination of single molecule force spectroscopy AFM and biochemical assays to show that the binding of TG-rich ssDNA triggers a mechanical switch in the RRM1 domain of TDP-43, toggling between an entropic spring devoid of mechanical stability and a shock absorber bound-form that resists unfolding forces of ∼40 pN. The fraction of mechanically resistant proteins correlates with an increasing length of the TGn oligonucleotide, demonstrating that protein mechanical stability is a direct reporter of nucleic acid binding. Steered molecular dynamics simulations on related RNA oligonucleotides reveal that the increased mechanical stability fingerprinting the holo-form is likely to stem from a unique scenario whereby the nucleic acid acts as a 'mechanical staple' that protects RRM1 from mechanical unfolding. Our approach highlights nucleic acid binding as an effective strategy to control protein nanomechanics. 2019-09-16T17:51:13Z 2019-09-16T17:51:13Z 2018-06-20 2019-09-16T17:51:13Z info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion 1948-7185 https://hdl.handle.net/2445/140129 689268 29924934 eng Versió postprint del document publicat a: https://doi.org/10.1021/acs.jpclett.8b01494 Journal of Physical Chemistry Letters, 2018, vol. 9, num. 14, p. 3800-3807 https://doi.org/10.1021/acs.jpclett.8b01494 info:eu-repo/grantAgreement/EC/H2020/731957/EU//MECHANO-CONTROL (c) American Chemical Society , 2018 info:eu-repo/semantics/openAccess 8 p. application/pdf American Chemical Society Articles publicats en revistes (Patologia i Terapèutica Experimental)