@article {2018|2134,
	title = {DNA Binding Induces a Nanomechanical Switch in the RRM1 Domain of TDP-43},
	journal = {J Phys Chem Lett},
	volume = {9},
	year = {2018},
	month = {Jul},
	pages = {3800-3807},
	abstract = {<p>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 \&sim;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 \&quot;mechanical staple\&quot; that protects RRM1 from mechanical unfolding. Our approach highlights nucleic acid binding as an effective strategy to control protein nanomechanics.</p>
},
	doi = {10.1021/acs.jpclett.8b01494},
	author = {Wang, Yong Jian and Rico-Lastres, Palma and Lezamiz, Ainhoa and Mora, Marc and Solsona, Carles and Guillaume Stirnemann and Garcia-Manyes, Sergi}
}
