Non-catalytic allostery in α-TAT1 by a phospho-switch drives dynamic microtubule acetylation

Autor: Abhijit Deb Roy, Evan G. Gross, Gayatri S. Pillai, Shailaja Seetharaman, Sandrine Etienne-Manneville, Takanari Inoue
Přispěvatelé: Johns Hopkins University School of Medicine [Baltimore], Johns Hopkins University (JHU), Polarité cellulaire, Migration et Cancer - Cell Polarity, Migration and Cancer, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This project was supported by American Heart Association fellowship 20POST35220046 (A. Deb Roy), discretionary funds (T. Inoue), the La Ligue contre le cancer (S-CR17017), and Centre National de la Recherche Scientifique and Institut Pasteur. S. Seetharaman is funded by the ITN PolarNet Marie Curie grant and Fondation pour la Recherche Médicale and is enrolled at the Ecole Doctorale Frontières du Vivant—Programme Bettencourt., We thank Allen Kim for discussions that led to initiation of this project, Amy F. Peterson for help with the kinase inhibitor assays. We thank Francesc Garcia-Gonzalo, Dipika Gupta, Yuta Nihongaki, and Helen D. Wu for constructive discussions, and Robert DeRose for proofreading.
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Journal of Cell Biology
Journal of Cell Biology, 2022, 221 (11), pp.e202202100. ⟨10.1083/jcb.202202100⟩
ISSN: 0021-9525
1540-8140
Popis: International audience; Spatiotemporally dynamic microtubule acetylation underlies diverse physiological and pathological events. Despite its ubiquity, the molecular mechanisms that regulate the sole microtubule acetylating agent, α-tubulin-N-acetyltransferase-1 (α-TAT1), remain obscure. Here, we report that dynamic intracellular localization of α-TAT1 along with its catalytic activity determines efficiency of microtubule acetylation. Specifically, we newly identified a conserved signal motif in the intrinsically disordered C-terminus of α-TAT1, consisting of three competing regulatory elements—nuclear export, nuclear import, and cytosolic retention. Their balance is tuned via phosphorylation by CDK1, PKA, and CK2, and dephosphorylation by PP2A. While the unphosphorylated form binds to importins and resides both in cytosol and nucleus, the phosphorylated form binds to specific 14-3-3 adapters and accumulates in the cytosol for maximal substrate access. Unlike other molecules with a similar phospho-regulated signal motif, α-TAT1 uniquely uses the nucleus as a hideout. This allosteric spatial regulation of α-TAT1 function may help uncover a spatiotemporal code of microtubule acetylation in normal and aberrant cell behavior.
Databáze: OpenAIRE
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