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.
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.
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