Document Type
Article
Publication Date
6-28-2022
Abstract
Cytoplasmic mislocalization of the TAR-DNA binding protein of 43 kDa (TDP-43) leads to large, insoluble aggregates that are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. Here, we study how importin α1/β recognizes TDP-43 bipartite nuclear localization signal (NLS). We find that the NLS makes extensive contacts with importin α1, especially at the minor NLS-binding site. NLS binding results in steric clashes with the C terminus of importin α1 that disrupts the TDP-43 N-terminal domain (NTD) dimerization interface. A putative phosphorylation site in the proximity of TDP-43 R83 at the minor NLS site destabilizes binding to importins by reducing the NLS backbone dynamics. Based on these data, we explain the pathogenic role of several post-translational modifications and mutations in the proximity of TDP-43 minor NLS site that are linked to disease and shed light on the chaperone activity of importin α1/β.
Recommended Citation
Doll, Steven G; Meshkin, Hamed; Bryer, Alexander J; Li, Fenglin; Ko, Ying-Hui; Lokareddy, Ravi K; Gillilan, Richard E; Gupta, Kushol; Perilla, Juan R; and Cingolani, Gino, "Recognition of the TDP-43 Nuclear Localization Signal by Importin α1/β" (2022). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 218.
https://jdc.jefferson.edu/bmpfp/218
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
35767952
Language
English
Comments
This article is the author's final published version in Cell Reports, Volume 39, Issue 13, June 2022, Article number 111007.
The published version is available at https://doi.org/10.1016/j.celrep.2022.111007.
© 2022 The Author(s)
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).