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http://hdl.handle.net/2445/140129
Title: | DNA binding induces a nanomechanical switch in the RRM1 domain of TDP-43 |
Author: | Wang, Yong Jian Rico-Lastres, Palma Lezamiz, Ainhoa Mora, Marc Solsona Sancho, Carles Stirnemann, Guillaume Garcia-Manyes, Sergi |
Keywords: | ADN Química Gens Proteïnes supressores de tumors DNA Chemistry Genes Tumor suppressor protein |
Issue Date: | 20-Jun-2018 |
Publisher: | American Chemical Society |
Abstract: | 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. |
Note: | Versió postprint del document publicat a: https://doi.org/10.1021/acs.jpclett.8b01494 |
It is part of: | Journal of Physical Chemistry Letters, 2018, vol. 9, num. 14, p. 3800-3807 |
URI: | http://hdl.handle.net/2445/140129 |
Related resource: | https://doi.org/10.1021/acs.jpclett.8b01494 |
ISSN: | 1948-7185 |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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