DNA binding induces a nanomechanical switch in the RRM1 domain of TDP-43
| Autor: | Palma Rico-Lastres, Marc Mora, Guillaume Stirnemann, Carles Solsona, Sergi Garcia-Manyes, Yongjian Wang, Ainhoa Lezamiz |
|---|---|
| Přispěvatelé: | Universitat de Barcelona |
| Předmět: |
0301 basic medicine
Ribonucleoside Diphosphate Reductase ADN Tumor Suppressor Proteins/chemistry 03 medical and health sciences chemistry.chemical_compound Molecular dynamics 0302 clinical medicine Protein Domains Molecule Humans General Materials Science Physical and Theoretical Chemistry Proteïnes supressores de tumors Mechanical Phenomena Oligonucleotide Tumor Suppressor Proteins Force spectroscopy Substrate (chemistry) RNA Química DNA Tumor suppressor protein DNA-Binding Proteins Chemistry 030104 developmental biology chemistry Genes Nucleic acid Biophysics 030217 neurology & neurosurgery Genes Switch DNA-Binding Proteins/chemistry Gens |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname The Journal of Physical Chemistry Letters Dipòsit Digital de la UB Universidad de Barcelona Wang, Y J, Rico-Lastres, P, Lezamiz, A, Mora, M, Solsona, C, Stirnemann, G & Garcia-Manyes, S 2018, ' DNA Binding Induces a Nanomechanical Switch in the RRM1 Domain of TDP-43 ', Journal of physical chemistry letters, vol. 9, no. 14, pp. 3800-3807 . https://doi.org/10.1021/acs.jpclett.8b01494 |
| DOI: | 10.1021/acs.jpclett.8b01494 |
| Popis: | 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 TG n 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. |
| Databáze: | OpenAIRE |
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