TY - JOUR
T1 - Non-catalytic allostery in α-TAT1 by a phospho-switch drives dynamic microtubule acetylation
AU - Roy, Abhijit Deb
AU - Gross, Evan G.
AU - Pillai, Gayatri S.
AU - Seetharaman, Shailaja
AU - Etienne-Manneville, Sandrine
AU - Inoue, Takanari
N1 - Funding Information:
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. The authors declare no competing financial interests.
Publisher Copyright:
© 2022 Deb Roy et al.
PY - 2022/11/7
Y1 - 2022/11/7
N2 - 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.
AB - 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.
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U2 - 10.1083/jcb.202202100
DO - 10.1083/jcb.202202100
M3 - Article
C2 - 36222836
AN - SCOPUS:85139804138
SN - 0021-9525
VL - 221
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 11
M1 - e202202100
ER -