Selective regulation of kinesin-5 function by β-tubulin carboxy-terminal tails DOI
Ezekiel C. Thomas, Jeffrey K. Moore

The Journal of Cell Biology, Journal Year: 2024, Volume and Issue: 224(3)

Published: Dec. 17, 2024

The tubulin code hypothesis predicts that tails create programs for selective regulation of microtubule-binding proteins, including kinesin motors. However, the molecular mechanisms determine and their relevance in cells are poorly understood. We report budding yeast kinesin-5 motors by β-tubulin tail. Cin8, but not Kip1, requires tail recruitment to mitotic spindle, creating a balance both spindle efficient progression. identify negatively charged patch mediates interaction with Cin8. Using vitro reconstitution genetically modified tubulin, we demonstrate increases Cin8 plus-end-directed velocity processivity. Finally, positively amino-terminal extension coordinates interactions Our work identifies mechanism underlying closely related how this promotes proper function spindle.

Language: Английский

The Tubulin Code, from Molecules to Health and Disease DOI Creative Commons

Elizabeth D. McKenna,

Stephanie L. Sarbanes,

Steven W. Cummings

et al.

Annual Review of Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 39(1), P. 331 - 361

Published: Oct. 16, 2023

Microtubules are essential dynamic polymers composed of α/β-tubulin heterodimers. They support intracellular trafficking, cell division, cellular motility, and other processes. In many species, both α-tubulin β-tubulin encoded by multiple genes with distinct expression profiles functionality. further diversified through abundant posttranslational modifications, which added removed a suite enzymes to form complex, stereotyped arrays. The genetic chemical diversity tubulin constitute code that regulates intrinsic microtubule properties is read effectors, such as molecular motors microtubule-associated proteins, provide spatial temporal specificity microtubules in cells. this review, we synthesize the rapidly expanding literature highlight limitations opportunities for field. As complex arrays underlie physiological processes, better understanding how cells employ has important implications human disease ranging from cancer neurological disorders.

Language: Английский

Citations

49
Tubulin polyglutamylation differentially regulates microtubule‐interacting proteins DOI Creative Commons
Mariya Genova, Lenka Grycová,

Verena Puttrich

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(5)

Published: Jan. 13, 2023

Language: Английский

Citations

33
Microtubule-associated protein MAP7 promotes tubulin posttranslational modifications and cargo transport to enable osmotic adaptation DOI
Yusheng Shen, Kassandra M Ori-McKenney

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(12), P. 1553 - 1570.e7

Published: April 3, 2024

Language: Английский

Citations

14
Elongator is a microtubule polymerase selective for polyglutamylated tubulin DOI Creative Commons
Vicente J. Planelles-Herrero, Mariya Genova, Lara K. Krüger

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

Elongator is a tRNA-modifying complex that regulates protein translation. Recently, moonlighting function of has been identified in regulating the polarization microtubule cytoskeleton during asymmetric cell division. induces symmetry breaking anaphase midzone by selectively stabilizing microtubules on one side spindle, contributing to downstream polarized segregation cell-fate determinants, and therefore fate determination. Here, we investigate how controls dynamics. binds both tip free GTP-tubulin heterodimers using two different subcomplexes, Elp123 Elp456, respectively. We show these activities must be coupled for decrease tubulin critical concentration elongation. As consequence, increases growth speed decreases catastrophe rate microtubules. Surprisingly, Elp456 subcomplex tails strong selectivity towards polyglutamylated tubulin. Hence, assembled become enriched with tubulin, as observed vitro, mouse Drosophila lines, well vivo Sensory Organ Precursor cells. Therefore, rewrites code growing microtubules, placing it at core cytoskeletal dynamics

Language: Английский

Citations

1
Doublecortin restricts neuronal branching by regulating tubulin polyglutamylation DOI Creative Commons
Muriel Sébastien, Alexandra Paquette, Emily N. P. Prowse

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 18, 2025

Doublecortin is a neuronal microtubule-associated protein that regulates microtubule structure in neurons. Mutations cause lissencephaly and subcortical band heterotopia by impairing migration. We use CRISPR/Cas9 to knock-out the gene induced pluripotent stem cells differentiate into cortical DCX-KO neurons show reduced velocities of nuclear movements an increased number neurites early development, consistent with previous findings. Neurite branching regulated host proteins, as well polymerization dynamics. However, EB comet dynamics are unchanged Rather, we observe significant reduction α-tubulin polyglutamylation Polyglutamylation levels rescued expression or TTLL11, glutamylase. Using U2OS orthogonal model system, DCX TTLL11 act synergistically promote polyglutamylation. propose acts positive regulator restricts neurite branching. Our results indicate unexpected role for homeostasis tubulin code. Lissencephaly severe neurodevelopmental disease often caused mutations Dcx gene. human cellular lissencephaly, authors report activating

Language: Английский

Citations

1
Glutamylation is a negative regulator of microtubule growth DOI
Jiayi Chen, Antonina Roll‐Mecak

Molecular Biology of the Cell, Journal Year: 2023, Volume and Issue: 34(7)

Published: April 19, 2023

Microtubules are noncovalent polymers built from αβ-tubulin dimers. The disordered C-terminal tubulin tails functionalized with multiple glutamate chains of variable lengths added and removed by tyrosine ligases (TTLLs) carboxypeptidases (CCPs). Glutamylation is abundant on stable microtubule arrays such as in axonemes axons, its dysregulation leads to human pathologies. Despite this, the effects glutamylation intrinsic dynamics unclear. Here we generate short long show that slows rate growth increases catastrophes a function levels. This implies higher stability glutamylated microtubules cells due effectors. Interestingly, EB1 minimally affected thus can report rates both unmodified microtubules. Finally, removal CCP1 5 synergistic occurs preferentially soluble tubulin, unlike TTLL enzymes prefer substrate preference establishes an asymmetry whereby once depolymerizes, released reset less-modified state, while polymerized accumulates mark. Our work shows modification directly affect furthers our understanding mechanistic underpinnings code.

Language: Английский

Citations

12
TUBB3 and KIF21A in neurodevelopment and disease DOI Creative Commons
Dharmendra Puri, Brenda J. Barry, Elizabeth C. Engle

et al.

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Aug. 4, 2023

Neuronal migration and axon growth guidance require precise control of microtubule dynamics microtubule-based cargo transport. TUBB3 encodes the neuronal-specific β-tubulin isotype III, TUBB3, a component neuronal microtubules expressed throughout life central peripheral neurons. Human pathogenic missense variants result in altered function cause errors either cranial and, to lesser extent, axons, or cortical organization, rarely both. Moreover, human KIF21A , which an anterograde kinesin motor protein that interacts directly with microtubules, alter can phenocopy variants. Here, we review reported variants, resulting phenotypes, corresponding functional studies both wildtype mutant proteins. We summarize evidence that, vitro mouse models, loss-of-function microtubule-kinesin interactions. Lastly, highlight additional might contribute our understanding relationship between specific tubulin isotypes proteins health disease.

Language: Английский

Citations

12
Structural basis for α-tubulin-specific and modification state-dependent glutamylation DOI

Kishore K. Mahalingan,

Danielle A. Grotjahn, Yan Li

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(11), P. 1493 - 1504

Published: April 24, 2024

Language: Английский

Citations

5
A family of carboxypeptidases catalyzing α- and β-tubulin tail processing and deglutamylation DOI Creative Commons
Simon Nicot, Ghislain Gillard, Hathaichanok Impheng

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(37)

Published: Sept. 13, 2023

Tubulin posttranslational modifications represent an important mechanism involved in the regulation of microtubule functions. The most widespread among them are detyrosination, α∆2-tubulin, and polyglutamylation. Here, we describe a family tubulin-modifying enzymes composed two closely related proteins, KIAA0895L KIAA0895, which have tubulin metallocarboxypeptidase activity thus were termed TMCP1 TMCP2, respectively. We show that (also known as MATCAP) acts α-tubulin detyrosinase also catalyzes α∆2-tubulin. In contrast, TMCP2 preferentially modifies βI-tubulin by removing three amino acids from its C terminus, generating previously unknown βI∆3 modification. βI∆3-tubulin is mostly found on centrioles mitotic spindles cilia. Moreover, demonstrate TMCPs remove polyglutamylation act deglutamylases. Together, our study describes identification comprehensive biochemical analysis type processing α- β-tubulin C-terminal tails deglutamylation.

Language: Английский

Citations

10
Microtubule polyglutamylation is an essential regulator of cytoskeletal integrity in Trypanosoma brucei DOI

Jana Jentzsch,

Hannes Wunderlich,

Marinus Thein

et al.

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(3)

Published: Jan. 11, 2024

ABSTRACT Tubulin polyglutamylation, catalysed by members of the tubulin tyrosine ligase-like (TTLL) protein family, is an evolutionarily highly conserved mechanism involved in regulation microtubule dynamics and function eukaryotes. In protozoan parasite Trypanosoma brucei, cytoskeleton essential for cell motility maintaining shape. a previous study, we showed that T. brucei TTLL6A TTLL12B are required to regulate at posterior pole. Here, using gene deletion, show polyglutamylase TTLL1 integrity organised structure pole, with phenotype distinct from observed TTLL6A- TTLL12B-depleted cells. Reduced polyglutamylation TTLL1-deficient cells also leads increased levels tyrosination, providing new evidence interplay between tyrosination detyrosination cycle polyglutamylation. We acts differentially on specific doublets flagellar axoneme, although absence appears have no measurable effect motility.

Language: Английский

Citations

4