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 and Helder Maiato ()
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Hugo Girão: University of Porto
Joana Macário-Monteiro: University of Porto
Ana C. Figueiredo: University of Porto
Ricardo Silva e Sousa: University of Porto
Elena Doria: University of Geneva
Vladimir Demidov: University of Pennsylvania
Hugo Osório: University of Porto
Ariana Jacome: University of Porto
Patrick Meraldi: University of Geneva
Ekaterina L. Grishchuk: University of Pennsylvania
Helder Maiato: University of Porto

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54155-8

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