DNA Binding Induces a Nanomechanical Switch in the RRM1 Domain of TDP-43

Yong Jian Wang, Palma Rico-Lastres, Ainhoa Lezamiz, Marc Mora, Carles Solsona, Guillaume Stirnemann, Sergi Garcia-Manyes

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
138 Downloads (Pure)

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 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.

Original languageEnglish
Pages (from-to)3800-3807
Number of pages8
JournalJournal of physical chemistry letters
Volume9
Issue number14
Early online dateJun 2018
DOIs
Publication statusPublished - 19 Jul 2018

Keywords

  • DNA-Binding Proteins/chemistry
  • Genes, Switch
  • Humans
  • Mechanical Phenomena
  • Protein Domains
  • Ribonucleoside Diphosphate Reductase
  • Tumor Suppressor Proteins/chemistry

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