7N9H
Structure of the mammalian importin a1 bound to the TDP-43 NLS
Summary for 7N9H
| Entry DOI | 10.2210/pdb7n9h/pdb |
| Related | 4UAF |
| Descriptor | Importin subunit alpha-1, TAR DNA-binding protein 43 (3 entities in total) |
| Functional Keywords | nuclear import, importin alpha, nls, tdp-43, protein transport |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 49127.23 |
| Authors | Doll, S.G.,Lokareddy, R.K.,Cingolani, G. (deposition date: 2021-06-17, release date: 2022-06-22, Last modification date: 2024-01-10) |
| Primary citation | Doll, S.G.,Meshkin, H.,Bryer, A.J.,Li, F.,Ko, Y.H.,Lokareddy, R.K.,Gillilan, R.E.,Gupta, K.,Perilla, J.R.,Cingolani, G. Recognition of the TDP-43 nuclear localization signal by importin alpha 1/ beta. Cell Rep, 39:111007-111007, 2022 Cited by PubMed 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. PubMed: 35767952DOI: 10.1016/j.celrep.2022.111007 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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