Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis

Liao, Shanhui; Rajendraprasad, Girish; Wang, Na; Eibes, Susana; Gao, J.; Yu, Huijuan; Wu, Gao; Tu, Xiaoming; Huang, Hongda; Barišić, Marin; Xu, Chao

doi:10.1038/s41422-019-0187-y

Cited by 61 publications

(107 citation statements)

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“…Indeed, MCAK was proposed to control the formation of robust KT-MT attachments both by regulating the length of non-kMTs through a role at MT plus ends (Domnitz et al, 2012), and by controlling chromosome directional switching by a specific role at centromeres (Kline-Smith et al, 2004; Wordeman et al, 2007). Additionally, α-tubulin detyrosination was recently shown to regulate MCAK activity required for normal astral MT length (Liao et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

“…In vitro reconstitution experiments have shown that MCAK activity is significantly suppressed by α-tubulin detyrosination (Peris et al, 2009; Sirajuddin et al, 2014), a posttranslational modification that accumulates on long-lived MTs (Nieuwenhuis and Brummelkamp, 2019). α-tubulin detyrosination has been recently implicated in mitosis and meiosis, neuronal processes and cognitive brain function, heart and skeletal muscle contraction, and cancer (Akera et al, 2017; Barisic et al, 2015; Chen et al, 2018; Erck et al, 2005; Kerr et al, 2015; Lafanechère et al, 1998; Liao et al, 2019; Pagnamenta et al, 2019; Robison et al, 2016). The detyrosination/tyrosination cycle involves the catalytic removal of the C-terminal tyrosine of most mammalian α-tubulin isoforms by tubulin carboxypeptidases, such as the recently identified Vasohibin (VASH) 1/VASH2-SVBP complexes (Aillaud et al, 2017; Nieuwenhuis et al, 2017), followed by retyrosination of soluble α-tubulin by tubulin tyrosine ligase (TTL; Ersfeld et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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α-Tubulin detyrosination impairs mitotic error correction by suppressing MCAK centromeric activity

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Rajendraprasad

et al. 2020

Journal of Cell Biology

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Incorrect kinetochore–microtubule attachments during mitosis can lead to chromosomal instability, a hallmark of human cancers. Mitotic error correction relies on the kinesin-13 MCAK, a microtubule depolymerase whose activity in vitro is suppressed by α-tubulin detyrosination—a posttranslational modification enriched on long-lived microtubules. However, whether and how MCAK activity required for mitotic error correction is regulated by α-tubulin detyrosination remains unknown. Here we found that detyrosinated α-tubulin accumulates on correct, more stable, kinetochore–microtubule attachments. Experimental manipulation of tubulin tyrosine ligase (TTL) or carboxypeptidase (Vasohibins-SVBP) activities to constitutively increase α-tubulin detyrosination near kinetochores compromised efficient error correction, without affecting overall kinetochore microtubule stability. Rescue experiments indicate that MCAK centromeric activity was required and sufficient to correct the mitotic errors caused by excessive α-tubulin detyrosination independently of its global impact on microtubule dynamics. Thus, microtubules are not just passive elements during mitotic error correction, and the extent of α-tubulin detyrosination allows centromeric MCAK to discriminate correct vs. incorrect kinetochore–microtubule attachments, thereby promoting mitotic fidelity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

α-Tubulin detyrosination impairs mitotic error correction by suppressing MCAK centromeric activity

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Orr

Rajendraprasad

et al. 2020

Journal of Cell Biology

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“…The alpha tubulin CTTs bearing terminal tyrosine are known to be recognized by CAP-Gly domains (Mishima et al, 2007), vasohibin or detyrosinase (Liao et al, 2019;Zhou et al, 2019), kinesin-13 and kinesin-2 motors (Sirajuddin et al, 2014). Additionally, the CAP-Gly domains bind to the carboxy-termini EEY motif of end-binding (EB) proteins, which is consensus to the alpha tubulin CTT terminus (Honnappa et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…Structural studies show that the sextette acidic motif (EEGEEY/F) of alpha tubulin CTT or the EEY motif of EBs are important for binding with CAP-Gly domain (Honnappa et al, 2006;Mishima et al, 2007). Vasohibin bound to alpha tubulin CTT complex structure also shows that the last five residues of alpha tubulin CTT (EGEEY) binds to the active site (Liao et al, 2019). In both cases the tyrosine recognition by CAP-Gly and VASH proteins reveals the importance of free mainchain carboxyl group of the terminal tyrosine residue.…”

Section: Discussionmentioning

confidence: 99%

Genetically encoded live cell sensor for tyrosinated microtubules

Kesarwani

Lama

Chandra

et al. 2020

Preprint

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Microtubule cytoskeleton exists in various biochemical forms in different cells due to tubulin post-translational modification (PTMs). These PTMs are known to affect microtubule stability, dynamics and interaction with MAPs and motors in a specific manner, widely known as tubulin code hypothesis. At present there exist no tool that can specifically mark tubulin PTMs in live cells, thus severely limiting our understanding of tubulin PTMs. Using yeast display library, we identified a binder against terminal tyrosine of alpha tubulin, a unique PTM site. Extensive characterization validates the robustness and non-perturbing nature of our binder as tyrosination sensor, a live cell tubulin nanobody specific towards tyrosinated or unmodified microtubules. Using which, in real time we followed nocodazole, colchicine and vincristine induced depolymerization events of unmodified microtubules, and found each distinctly perturb microtubule polymer. Together, our work describes the tyrosination sensor and potential applications to study microtubule and PTM processes in living cells.

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“…In vitro reconstitution experiments have shown that MCAK activity is significantly suppressed by microtubule detyrosination (Peris et al, 2009;Sirajuddin et al, 2014), a posttranslational modification on long-lived microtubules (Nieuwenhuis and Brummelkamp, 2019). Microtubule detyrosination has been recently implicated in mitosis and meiosis, neuronal processes and cognitive brain function, heart and skeletal mucle contraction, and cancer (Akera et al, 2017;Barisic et al, 2015;Chen et al, 2018;Erck et al, 2005;Kerr et al, 2015;Lafanechere et al, 1998;Liao et al, 2019;Pagnamenta et al, 2019;Robison et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Microtubule tyrosination/detyrosination specifies a mitotic error code

Ferreira

Orr

Rajendraprasad

et al. 2019

Preprint

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Incorrect kinetochore-microtubule attachments during mitosis can lead to chromosomal instability, a hallmark of human cancers. Mitotic error correction relies on the kinesin-13 MCAK, a microtubule depolymerase whose activity in vitro is suppressed by α-tubulin detyrosination -a post-translational modification enriched on long-lived microtubules.However, whether and how MCAK activity required for mitotic error correction is regulated by microtubule tyrosination/detyrosination remains unknown. Here we found that microtubule detyrosination accumulates on correct, more stable, kinetochore-microtubule attachments, whereas constitutively high microtubule detyrosination near kinetochores compromised efficient error correction. Rescue experiments suggest that mitotic errors due to excessive microtubule detyrosination result from suppression of MCAK activity, without globally affecting kinetochore microtubule half-life. Importantly, MCAK centromeric activity was required and sufficient to rescue mitotic errors due to excessive microtubule detyrosination.Thus, microtubules are not just passive elements during mitotic error correction, and their tyrosination/detyrosination works as a 'mitotic error code' that allows centromeric MCAK to discriminate correct and incorrect kinetochore-microtubule attachments, thereby promoting mitotic fidelity.

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Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis

Cited by 61 publications

References 68 publications

α-Tubulin detyrosination impairs mitotic error correction by suppressing MCAK centromeric activity

α-Tubulin detyrosination impairs mitotic error correction by suppressing MCAK centromeric activity

Genetically encoded live cell sensor for tyrosinated microtubules

Microtubule tyrosination/detyrosination specifies a mitotic error code

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