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
  • 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. [email protected].
  • 8. IBMC-Institute for Molecular and Cell Biology, University of Porto, Rua Alfredo Allen 208, 4200-135, Porto, Portugal. [email protected].
  • 9. Cell Division Group, Experimental Biology Unit, Department of Biomedicine, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal. [email protected].
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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