Title:
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DNA binding induces a nanomechanical switch in the RRM1 domain of TDP-43
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Author:
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Wang, Yong Jian; Rico-Lastres, Palma; Lezamiz, Ainhoa; Mora. Marc; Solsona Sancho, Carles; Stirnemann, Guillaume; Garcia-Manyes, Sergi
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Abstract:
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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. |
Subject(s):
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-ADN -Química -Gens -Proteïnes supressores de tumors -DNA -Chemistry -Genes -Tumor suppressor protein |
Rights:
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(c) American Chemical Society , 2018
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Document type:
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Article Article - Accepted version |
Published by:
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American Chemical Society
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