9B4Y

Cryo-EM structure of importin alpha-1/beta bound to TDP-43

Summary for 9B4Y

• Entry DOI: 10.2210/pdb9b4y/pdb
• EMDB information: 44191
• Descriptor: Importin subunit beta-1, Importin subunit alpha-1 (2 entities in total)
• Functional Keywords: importins, transport protein, tdp-43
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 102620.18

Authors

Ko, Y.,Cingolani, G. (deposition date: 2024-03-21, release date: 2025-03-26, Last modification date: 2026-04-08)

Primary citation

Ko, Y.H.,Lokareddy, R.K.,Doll, S.G.,Yeggoni, D.P.,Girdhar, A.,Mawn, I.,Klim, J.R.,Rizvi, N.F.,Meyers, R.,Gillilan, R.E.,Guo, L.,Cingolani, G.
Single Acetylation-mimetic Mutation in TDP-43 Nuclear Localization Signal Disrupts Importin alpha 1/ beta Signaling.
J.Mol.Biol., 436:168751-168751, 2024

PubMed Abstract: Cytoplasmic aggregation of the TAR-DNA binding protein of 43 kDa (TDP-43) is the hallmark of sporadic amyotrophic lateral sclerosis (ALS). Most ALS patients with TDP-43 aggregates in neurons and glia do not have mutations in the TDP-43 gene but contain aberrantly post-translationally modified TDP-43. Here, we found that a single acetylation-mimetic mutation (K82Q) near the TDP-43 minor Nuclear Localization Signal (NLS) box, which mimics a post-translational modification identified in an ALS patient, can lead to TDP-43 mislocalization to the cytoplasm and irreversible aggregation. We demonstrate that the acetylation mimetic disrupts binding to importins, halting nuclear import and preventing importin α1/β anti-aggregation activity. We propose that perturbations near the NLS are an additional mechanism by which a cellular insult other than a genetically inherited mutation leads to TDP-43 aggregation and loss of function. Our findings are relevant to deciphering the molecular etiology of sporadic ALS.

PubMed: 39181183
DOI: 10.1016/j.jmb.2024.168751

Experimental method

ELECTRON MICROSCOPY (3.74 Å)