Posttranslational modification of microtubules by the MATCAP detyrosinase

Landskron, Lisa; Bak, Jitske; Adamopoulos, Athanassios; Kaplani, Konstantina; Moraiti, Maria; Hengel, Lisa G. van den; Song, Ji‐Ying; Bleijerveld, Onno B.; Nieuwenhuis, Joppe; Heidebrecht, Tatjana; Henneman, Linda; Moutin, Marie‐Jo; Barišić, Marin; Taraviras, Stavros; Perrakis, Anastassis; Brummelkamp, Thijn R.

doi:10.1126/science.abn6020

Cited by 53 publications

(67 citation statements)

References 66 publications

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“…This mechanism could have implications in the diversity of microtubules reported in cells (for a review see (Roll-Mecak, 2019; Roll-Mecak, 2020)), which likely contain different compositions of detyrosinating enzymes. With the very recent discovery of the third detyrosinating enzyme MATCAP (Landskron et al, 2022), which uses a fundamentally different catalytic mechanism (being a metalloprotease instead of a cysteine protease) and adopts an alternative microtubule-binding mode and a different way of detyrosinating microtubules, the complexity of microtubule detyrosination in cells may even be more complex. These different microtubule detyrosinating enzymes likely encode numerous subpopulations of microtubules bearing different tyrosination signal patterns that, when read by effectors, could fine-tune physiological processes in specific regions of the cell.…”

Section: Discussionmentioning

confidence: 99%

VASH1-SVBP and VASH2-SVBP generate different detyrosination profiles on microtubules

Ramirez-Rios

Choi

Sanyal

et al. 2022

Preprint

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The detyrosination/tyrosination cycle of alpha tubulin is critical for proper cell functioning. VASH1-SVBP and VASH2-SVBP are ubiquitous enzyme complexes involved in microtubule detyrosination. However, little is known about their mode of action. Here, we show in reconstituted systems and in cells that VASH1-SVBP and VASH2-SVBP drive global and local detyrosination of microtubules, respectively. We solved the cryo-electron microscopy structure of human VASH2-SVBP bound to microtubules, revealing a different microtubule-binding configuration of its central catalytic region compared to VASH1-SVBP. We further show that the divergent mode of detyrosination between the two enzymes is correlated with the microtubule-binding properties of their disordered N- and C-terminal regions. Specifically, the N-terminal region is responsible for a significantly longer residence time of VASH2-SVBP on microtubules compared to VASH1-SVBP. We suggest that this VASH domain is critical for microtubule-detachment and diffusion of VASH-SVBP enzymes on the lattice. Together, our results suggest a mechanism by which these enzymes could generate distinct microtubule subpopulations and confined areas of detyrosinated lattices to drive various microtubule-based cellular functions.

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Section: Discussionmentioning

confidence: 99%

VASH1-SVBP and VASH2-SVBP generate different detyrosination profiles on microtubules

Ramirez-Rios

Choi

Sanyal

et al. 2022

Preprint

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“…After more than 40 years of research, the molecular nature of this enzyme was recently discovered ( Aillaud et al, 2017 ; Nieuwenhuis et al, 2017 ) and knowledge of its structure ( Adamopoulos et al, 2019 ; Li et al, 2019 ; Wang et al, 2019 ) should now facilitate the search for more selective inhibitors. Yet, since then, another enzyme with TCP activity ( Landskron et al, 2022 ) has been described, which broadens the field of research for such inhibitors and will require clarification of their therapeutic applications.…”

Section: Towards a Surgical Strike Of Diseased Cells Onlymentioning

confidence: 99%

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

Lafanéchère

2022

Front. Pharmacol.

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Compounds targeting microtubules are widely used in cancer therapy with a proven efficacy. However, because they also target non-cancerous cells, their administration leads to numerous adverse effects. With the advancement of knowledge on the structure of tubulin, the regulation of microtubule dynamics and their deregulation in pathological processes, new therapeutic strategies are emerging, both for the treatment of cancer and for other diseases, such as neuronal or even heart diseases and parasite infections. In addition, a better understanding of the mechanism of action of well-known drugs such as colchicine or certain kinase inhibitors contributes to the development of these new therapeutic approaches. Nowadays, chemists and biologists are working jointly to select drugs which target the microtubule cytoskeleton and have improved properties. On the basis of a few examples this review attempts to depict the panorama of these recent advances.

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“…The tyrosination/ detyrosination (Tyr/deTyr) cycle is regulated by the vasohibinsmall vasohibin binding protein complexes (VASH1/2-SVBP) and MATCAP, which remove the terminal tyrosine from the αtubulin C-terminal tail, while tubulin tyrosine ligase (TTL) readds it. VASH-SVBP and MATCAP act on MTs, while TTL acts on soluble tubulin dimers (Kreis, 1987;Webster et al, 1987;Prota et al, 2013;Aillaud et al, 2017;Nieuwenhuis et al, 2017;Landskron et al, 2022). The pool of detyrosinated tubulin can be further processed by cytosolic carboxy peptidases (CCPs) from the deglutamylase family, that remove the terminal glutamate, turning detyrosinated into Δ2 tubulin (Rogowski et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer’s disease

Martínez-Hernández

Parato

Sharma

et al. 2022

Front. Cell Dev. Biol.

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Microtubules (MTs) support a variety of neuronal functions, such as maintenance of cell structure, transport, and synaptic plasticity. Neuronal MTs are highly heterogeneous due to several tubulin isotypes and the presence of multiple post-translational modifications, such as detyrosination and acetylation. The tubulin tyrosination/detyrosination cycle is a key player in the maintenance of MT dynamics, as tyrosinated tubulin is associated with more dynamic MTs, while detyrosinated tubulin is linked to longer lived, more stable MTs. Dysfunction of tubulin re-tyrosination was recently correlated to Alzheimer’s disease progression. The implication of tubulin acetylation in Alzheimer’s disease has, however, remained controversial. Here, we demonstrate that tubulin acetylation accumulates in post-mortem brain tissues from Alzheimer’s disease patients and human neurons harboring the Alzheimer’s familial APP-V717I mutation. We further show that tubulin re-tyrosination, which is defective in Alzheimer’s disease, can control acetylated tubulin in primary neurons irrespective of the levels of the enzymes regulating tubulin acetylation, suggesting that reduced MT dynamics associated with impaired tubulin re-tyrosination might contribute to the accumulation of tubulin acetylation that we detected in Alzheimer’s disease.

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Posttranslational modification of microtubules by the MATCAP detyrosinase

Cited by 53 publications

References 66 publications

VASH1-SVBP and VASH2-SVBP generate different detyrosination profiles on microtubules

VASH1-SVBP and VASH2-SVBP generate different detyrosination profiles on microtubules

The microtubule cytoskeleton: An old validated target for novel therapeutic drugs

Crosstalk between acetylation and the tyrosination/detyrosination cycle of α-tubulin in Alzheimer’s disease

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