Recognition of the TDP-43 nuclear localization signal by importin α1/β

• DOI: 10.1016/j.celrep.2022.111007
• Publication Date: 2022-06-28T20:14:20Z
• Authors: Steven G. Doll; Hamed Meshkin; Alexander J. Bryer; Fenglin Li; Ying-Hui Ko; Ravi K. Lokareddy; Richard E. Gillilan; Kushol Gupta; Juan R. Perilla; Gino Cingolani
• Keywords: NLS; Importin; Ran

Cytoplasmic mislocalization of the TAR-DNA binding protein 43 kDa (TDP-43) leads to large, insoluble aggregates that are a hallmark amyotrophic lateral sclerosis and frontotemporal dementia. Here, we study how importin α1/β recognizes TDP-43 bipartite nuclear localization signal (NLS). We find NLS makes extensive contacts with α1, especially at minor NLS-binding site. results in steric clashes C terminus α1 disrupts N-terminal domain (NTD) dimerization interface. A putative phosphorylation site proximity R83 destabilizes importins by reducing backbone dynamics. Based on these data, explain pathogenic role several post-translational modifications mutations linked disease shed light chaperone activity α1/β.