Document type
ArticleVersion
Accepted versionPublication date
All rights reserved
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/140129
DNA binding induces a nanomechanical switch in the RRM1 domain of TDP-43
Journal Title
Director/Tutor
Journal ISSN
Volume Title
Related resource
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.
Subject
Subject (English)
Citation
Citation
WANG, Yong Jian, et al. DNA binding induces a nanomechanical switch in the RRM1 domain of TDP-43. Journal of Physical Chemistry Letters. 2018. Vol. 9, num. 14, pags. 3800-3807. ISSN 1948-7185. [consulted: 12 of August of 2026]. Available at: https://hdl.handle.net/2445/140129