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| Title | Single Acetylation-mimetic Mutation in TDP-43 Nuclear Localization Signal Disrupts Importin α1/β Signaling. |
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| Journal, issue, pages | J Mol Biol, Vol. 436, Issue 20, Page 168751, Year 2024 |
| Publish date | Oct 15, 2024 |
 Authors | Ying-Hui Ko / Ravi K Lokareddy / Steven G Doll / Daniel P Yeggoni / Amandeep Girdhar / Ian Mawn / Joseph R Klim / Noreen F Rizvi / Rachel Meyers / Richard E Gillilan / Lin Guo / Gino Cingolani /  |
| 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 ...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. |
 External links | J Mol Biol / PubMed:39181183 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.74 Å |
| Structure data | EMDB-44191, PDB-9b4y: |
| Source |
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 Keywords | TRANSPORT PROTEIN / Importins / TDP-43 |
homo sapiens (human)