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Post-translational modifications regulate microtubule function

Key Points

  • The carboxy-terminal tails of α- and β-tubulin are essential for microtubule function. They lie on the outer surface of the microtubule where they can influence the binding of associated proteins.

  • With the exception of acetylation, the post-translational modifications of microtubules — that is, detyrosination/tyrosination, formation of Δ2-tubulin, polyglutamylation and polyglycylation — are all located in the carboxy-terminal tails.

  • Acetylation of α-tubulin can be abolished without consequences in Tetrahymena, but it seems to have a function in cell motility. Two histone deacetylases, HDAC6 and SIRT2, have been shown to function as tubulin deacetylases.

  • Genetic analysis of polyglycylation in Tetrahymena demonstrates its essential function in the organization of axonemes, cell motility and cytokinesis.

  • Polyglutamylation can influence the binding of structural and motor microtubule-associated proteins (MAPs) to microtubules. Antibody-injection studies indicate an important role for polyglutamylation in centriole stability.

  • The functional role of the tyrosination cycle of tubulin is still unclear; cells cultured with low activity of the tubulin tyrosine ligase (TTL) enzyme show no obvious defects. TTL-knockout mice, however, die early in development owing to an as-yet-uncharacterized defect.

Abstract

The αβ-tubulin heterodimer, the building block of microtubules, is subject to a large number of post-translational modifications, comparable in diversity to the intensively studied histone modifications. Although these unusual modifications are conserved throughout evolution, their functions have remained almost completely elusive. Recently, however, important advances in the understanding of how tubulin modifications regulate function and organization have been made.

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Figure 1: Conservation of modification sites and localization of carboxy-terminal domains.
Figure 2: Polyglycylation mutants affect cytokinesis in Tetrahymena.
Figure 3: The tyrosination cycle of α-tubulin.
Figure 4: Differential distribution of modified microtubules within the flagellar axoneme.
Figure 5: Proposed roles for post-translationally modified microtubules.

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Acknowledgements

The authors wish to thank G. Barnes and D. Drubin for critical reading of the manuscript. We thank E. Nogales, R. Thazhath and J. Gaertig for providing figures and J. Wehland, D. Job and B. Eddé for communicating results prior to publication. We apologize to all authors whose work could not be cited due to space limitations. S.W. is supported by a fellowship of the Deutsche Forschungsgemeinschaft (DFG).

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Correspondence to Stefan Westermann.

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DATABASES

Interpro

α-tubulin

β-tubulin

δ-tubulin

ε-tubulin

γ-tubulin

ζ-tubulin

Saccharomyces genome database

Sir2

OMIM

PKD

Swiss-Prot

FtsZ

HDAC6

MAP1B

NAP1

NAP2

Nek

Nek1

SIRT2

tau

TTL

Glossary

MITOTIC SPINDLE

A bipolar array of microtubules that functions to move the duplicated chromosomes during mitosis and meiosis.

AXONEME

A bundle of microtubules and associated proteins that form the core of a flagellum or cilium.

CILIA

Hair-like extensions of cells, which contain a microtubular axoneme. Beating movements of cilia are responsible for swimming.

FLAGELLA

Long protrusions that contain a microtubular axoneme, the beating of which can drive a cell through liquid media. Note that bacterial flagella are constructed very differently from eukaryotic flagella.

PROTISTS

Single-celled eukaryotic organisms that are either free living or parasitic.

TETRAHYMENA THERMOPHILA

Unicellular ciliated eukaryote.

CHLAMYDOMONAS REINHARDTII

Flagellated green algae that are often used as a model organism to study flagellar assembly and architecture.

siRNA

Small interfering RNA that is used to specifically reduce protein expression by degradation of the corresponding messenger RNA.

HETEROKARYONS

Multinucleate cells containing nuclei of more than one genotype.

9 + 2

The typical organization of microtubules within an axoneme, with 9 outer doublets and one pair of central microtubules.

BASAL BODY

A short cylindrical array of microtubules that is found at the base of cilia and flagella. It is closely related, in structure, to a centriole.

CENTRIOLES

Usually found in the centre of centrosomes in animal cells, the two centrioles contain triplet microtubules and are located orthogonally to each other. Centrioles are closely related to basal bodies.

MIDBODY

The structure formed at the end of animal-cell cytokinesis, which tethers the cells and can persist for some time.

HELA CELLS

A cultured human epithelial cell line derived from a cervical carcinoma.

ISOELECTRIC FOCUSING

A method to separate proteins according to their isoelectric point; it is carried out by electrophoresis in a pH gradient.

EDMAN DEGRADATION

A classical method of peptide sequencing by stepwise degradation and identification of the amino-terminal amino acid.

TANDEM-MS

(or MS/MS). A variant of mass spectrometry that is used to sequence peptides and determine their structure.

TRYPANOSOMES

Flagellate protozoans, ubiquitous parasites of insects, birds and mammals; some species are important human pathogens.

CENTROSOME

The main microtubule-organizing centre of animal cells. It functions as a spindle pole during mitosis.

POLYCYSTIC KIDNEY DISEASE

(PKD) A genetic disease that is characterized by the formation of multiple cysts in the kidney, which ultimately leads to loss of renal function and the need for dialysis or transplantation.

KINESIN

A microtubular motor protein that generally moves towards the plus end of microtubules.

DIPLOMONAD

A primitive single-celled organism with two nuclei and no mitochondria; includes the human intestinal parasite Giardia lamblia.

B-TUBULES

Incomplete, 10-protofilament microtubules that comprise a part of the outer axoneme doublets.

RHO-FAMILY GTPases

Ras-related small GTPases that mediate signal transduction to cause rearrangements of the actin- and microtubule-filament network.

FORMINS

Rho-GTPase effector proteins that link signal-transduction pathways to actin assembly proteins.

PLUS END

The end of a microtubule at which addition of tubulin dimers occurs most rapidly.

INTERMEDIATE FILAMENTS

10-nm protein filaments that constitute one of the three main cytoskeletal filaments of eukaryotic cells.

MYOBLAST

A specialized cell type that, by fusion with other myoblasts, forms myotubes that eventually differentiate into skeletal-muscle fibres.

ASTRAL MICROTUBULES

A subset of microtubules within the mitotic spindle that are not attached to the kinetochore but extend from the centrosome to the cell cortex.

BUD NECK

A constriction between the mother and daughter cell in the budding yeast Saccharomyces cerevisiae.

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Westermann, S., Weber, K. Post-translational modifications regulate microtubule function. Nat Rev Mol Cell Biol 4, 938–948 (2003). https://doi.org/10.1038/nrm1260

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