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  3. α-tubulin detyrosination fine-tunes kinetochore-microtubule attachments

α-tubulin detyrosination fine-tunes kinetochore-microtubule attachments

  • Nat Commun. 2024 Nov 9;15(1):9720. doi: 10.1038/s41467-024-54155-8.
Hugo Girão 1 2,  Joana Macário-Monteiro 1 2,  Ana C Figueiredo 1 2,  Ricardo Silva E Sousa 1 2 3,  Elena Doria 4 5,  Vladimir Demidov 3,  Hugo Osório 1 6,  Ariana Jacome 1 2,  Patrick Meraldi 4 5,  Ekaterina L Grishchuk 3,  Helder Maiato 7 8 9
Affiliations

Affiliations

  • 1 i3S-Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
  • 2 IBMC-Institute for Molecular and Cell Biology, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal.
  • 3 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 4 Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland.
  • 5 Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva, 1211 Geneva 4, Geneva, Switzerland.
  • 6 IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, University of Porto, 4200-135, Porto, Portugal.
  • 7 i3S-Institute for Research and Innovation in Health, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal. maiato@i3s.up.pt.
  • 8 IBMC-Institute for Molecular and Cell Biology, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal. maiato@i3s.up.pt.
  • 9 Cell Division Group, Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. maiato@i3s.up.pt.
PMID: 39521805 DOI: 10.1038/s41467-024-54155-8
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.

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