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Open AccessArticle

Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43

1
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Biochemistry, University of Florence, Viale G. B. Morgagni 50, 50134 Florence, Italy
2
Living Systems Institute, University of Exeter, Stocker Road, Exeter EX4 4QD, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(17), 6259; https://doi.org/10.3390/ijms21176259
Received: 6 August 2020 / Revised: 21 August 2020 / Accepted: 25 August 2020 / Published: 29 August 2020
(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)
TAR DNA-binding protein 43 (TDP-43) is a 414-residue long nuclear protein whose deposition into intraneuronal insoluble inclusions has been associated with the onset of amyotrophic lateral sclerosis (ALS) and other diseases. This protein is physiologically a homodimer, and dimerization occurs through the N-terminal domain (NTD), with a mechanism on which a full consensus has not yet been reached. Furthermore, it has been proposed that this domain is able to affect the formation of higher molecular weight assemblies. Here, we purified this domain and carried out an unprecedented characterization of its folding/dimerization processes in solution. Exploiting a battery of biophysical approaches, ranging from FRET to folding kinetics, we identified a head-to-tail arrangement of the monomers within the dimer. We found that folding of NTD proceeds through the formation of a number of conformational states and two parallel pathways, while a subset of molecules refold slower, due to proline isomerism. The folded state appears to be inherently prone to form high molecular weight assemblies. Taken together, our results indicate that NTD is inherently plastic and prone to populate different conformations and dimeric/multimeric states, a structural feature that may enable this domain to control the assembly state of TDP-43. View Full-Text
Keywords: amyotrophic lateral sclerosis; folding intermediate; misfolding; self-assembly; neurodegeneration; proteinopathy; native-like state; chevron plot amyotrophic lateral sclerosis; folding intermediate; misfolding; self-assembly; neurodegeneration; proteinopathy; native-like state; chevron plot
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MDPI and ACS Style

Vivoli-Vega, M.; Guri, P.; Chiti, F.; Bemporad, F. Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43. Int. J. Mol. Sci. 2020, 21, 6259. https://doi.org/10.3390/ijms21176259

AMA Style

Vivoli-Vega M, Guri P, Chiti F, Bemporad F. Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43. International Journal of Molecular Sciences. 2020; 21(17):6259. https://doi.org/10.3390/ijms21176259

Chicago/Turabian Style

Vivoli-Vega, Mirella; Guri, Prandvera; Chiti, Fabrizio; Bemporad, Francesco. 2020. "Insight into the Folding and Dimerization Mechanisms of the N-Terminal Domain from Human TDP-43" Int. J. Mol. Sci. 21, no. 17: 6259. https://doi.org/10.3390/ijms21176259

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