Nature Communications (Nov 2024)

α-tubulin detyrosination fine-tunes kinetochore-microtubule attachments

  • Hugo Girão,
  • Joana Macário-Monteiro,
  • Ana C. Figueiredo,
  • Ricardo Silva e Sousa,
  • Elena Doria,
  • Vladimir Demidov,
  • Hugo Osório,
  • Ariana Jacome,
  • Patrick Meraldi,
  • Ekaterina L. Grishchuk,
  • Helder Maiato

DOI
https://doi.org/10.1038/s41467-024-54155-8
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 19

Abstract

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Abstract Post-translational cycles of α-tubulin detyrosination and tyrosination generate microtubule diversity, the cellular functions of which remain largely unknown. Here we show that α-tubulin detyrosination regulates kinetochore-microtubule attachments to ensure normal chromosome oscillations and timely anaphase onset during mitosis. Remarkably, detyrosinated α-tubulin levels near kinetochore microtubule plus-ends depend on the direction of chromosome motion during metaphase. Proteomic analyses unveil that the KNL-1/MIS12/NDC80 (KMN) network that forms the core microtubule-binding site at kinetochores and the microtubule-rescue protein CLASP2 are enriched on tyrosinated and detyrosinated microtubules during mitosis, respectively. α-tubulin detyrosination enhances CLASP2 binding and NDC80 complex diffusion along the microtubule lattice in vitro. Rescue experiments overexpressing NDC80, including variants with slower microtubule diffusion, suggest a functional interplay with α-tubulin detyrosination for the establishment of a labile kinetochore-microtubule interface. These results offer a mechanistic explanation for how different detyrosinated α-tubulin levels near kinetochore microtubule plus-ends fine-tune load-bearing attachments to both growing and shrinking microtubules.