Tubulin and Microtubules


Microtubules are found in almost all types of eukaryotic cell. Their principal constituents are the highly conserved proteins of the tubulin family, in the form of longitudinal protofilaments of tubulin heterodimers. The conserved lateral interactions produce a characteristic 2D lattice. Tubulin structure and conformational changes are now known to atomic resolution. Its GTP‐dependent dynamic self‐assembly and disassembly is modulated by a host of other proteins. This dynamic activity and a more passive role as tracks for interaction with motor proteins, kinesin and dynein, allow microtubules to perform vital roles in various forms of cell motility. They are an essential component of cell division, provide oriented tracks for the transport of cellular organelles and vesicles and are responsible for the relative positioning of cellular compartments. Thus, they are important targets in the control of cancer cells, as their essential activity is severely affected by a variety of drugs.

Key Concepts

  • Tubulin heterodimers, consisting of highly homologous α‐ and β‐tubulin monomers, self‐assemble into a unique lattice with polar longitudinal ‘protofilaments’
  • The assembled sheet has a slightly variable curvature, producing microtubules, with around 13 protofilaments but not strictly defined unless they are grown from a γ‐tubulin template or given a curvature appropriate to exactly 13 protofilaments by accessory proteins
  • The structure of microtubules has been solved to near‐atomic level both with GTP homologues bound to β‐tubulin and with GDP bound; also a depolymerised protofilament structure in a longitudinally curved conformation is known
  • Hydrolysis of bound GTP enables microtubules to assemble with ‘dynamic instability’, behaviour that depends on stochastic disassembly when the GTP ‘cap’ is lost from a growing end
  • Microtubule behaviour is modified by many different accessory proteins that may act just at the tips or everywhere on the lattice wall
  • To play different roles according to their positions in cells, the properties of microtubules may vary owing to different tubulin isotypes and be modified by a wide range of associated proteins
  • Changes can also vary with time (‘ageing’) as a result of post‐translational modification of tubulin and of some accessory proteins
  • Microtubules are employed in axonemes of cilia and flagella, where the motor protein dynein interacts with them to produce beating while other linking components help control the wave‐form
  • Cytoplasmic microtubules provide tracks for vesicles and other cargoes driven by kinesins and cytoplasmic dynein
  • Mitotic and meiotic spindles are assembled from microtubules, which interact with kinetochores and with multiple motor proteins
  • Microtubules are susceptible to many small molecules that depolymerise or hyperstabilise them and thus serve as anti‐cancer drugs.

Keywords: dynamic instability; motility; microtubule lattices; GTP hydrolysis

Figure 1. (a,b) Microtubules in cells viewed by immunofluorescence light microscopy. DNA is labelled in blue, all microtubules in green, and glutamylated tubulin in red. The central spindle of the cell in anaphase (a) and the midbody microtubules between cells in the final stage of division (b) appear yellow (green plus red), where the tubulin is more modified. (c) A single microtubule as seen by cryo‐electron microscopy. (a,b) Courtesy of Dr Carsten Janke. (c) Taken by Dr Keiko Hirose.
Figure 2. Structure of microtubules. (a) Atomic structure of the αβ‐tubulin heterodimer (PDB code 1JFF) shown as a ribbon diagram; GTPase domains in red, intermediate/activation domains in blue, C‐terminal/outer‐surface domains in green, and central helices in yellow. (b) Assembly of heterodimers into longitudinal protofilaments, which in turn associate into sheets and microtubules. Side‐to‐side association of the protofilaments in two possible ways can produce an A‐lattice (symmetrical for the 13‐protofilament microtubule shown) or a B‐lattice (with an A‐lattice‐like seam for 13 or 14 protofilaments, though not for 15 or 16). (c) Typical features of the two ends of a microtubule. The minus ends cells are mostly capped by a γ‐tubulin ring complex that provides a template for the growth of 13 protofilaments. The plus ends often remain free to grow by addition of heterodimers to sites with GTP bound on the exposed β‐tubulin and shrink by loss of subunits that have caused GTP‐hydrolysis.
Figure 3. Structural changes in protofilaments. (a) αβ‐tubulin heterodimers as viewed from inside a microtubule. The two globular domains in each subunit are coloured red (GTPase) and blue; GDP, bound to the GTPase domains, is shown as space‐filling atoms (grey). The globular domains are separated by the core helix (yellow); Taxol binds in an adjacent pocket, where it promotes the straight conformation. The M‐loops make lateral contact with loops in the GTPase domains of another protofilament. At an active interface within a protofiilament, the T7 loop of α‐tubulin triggers GTP hydrolysis between heterodimers. The spacing there is greater when GTP is present than it is after hydrolysis, when loops around the nucleotide change conformation. The passive intra‐dimer interface does not change. (b) Stathmin (in grey) binds to two tubulin heterodimers in a curved conformation, in which there is bending at the passive and active interfaces. The binding sites are shown of some drugs (colchicine and vinblastine) that promote curvature and hence depolymerisation. Stathmin sequesters heterodimers to reduce the concentration of tubulin available for assembly.
Figure 4. Diagrams showing how the orientations of microtubules vary during the cell cycle. (a) A typical motile cell, such as a fibroblast, in interphase. Most microtubules grow out towards the cell periphery keeping their minus ends associated with the centrosomal region. This structure contains a pair of centrioles surrounded by a cloud of proteins that include γ‐tubulin. The plus ends grow out dynamically, with specific proteins tracking the microtubule tips. These may interact eventually with specific membrane‐associated proteins or with the cortical layer of actin filaments (yellow). See also: Cell Locomotion (b) Vertebrate mitotic spindle depicted in metaphase (chromosomes paired at the mid‐plane of the spindle) and in anaphase (chromosomes moving towards the poles). The centrosome at each pole, containing one old and one new centriole, acts as a focus for microtubule minus ends.
Figure 5. (a) Cross section through a typical axoneme, viewed from the tip, that is, from the plus ends of the microtubules. Microtubules were first seen in flagellar and ciliary axonemes. (b) Enlarged cross section of one of the doublet microtubules. Nine doublet microtubules and a central core structure are linked together by a complex variety of accessory molecules. Centrioles (Figure ) are built from nine triplet microtubules, with a C‐microtubule attached to each B‐microtubule; their A tubules do not have dynein arms attached.


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Further Reading

Amos LA (2011) What tubulin drugs tell us about microtubule structure and dynamics. Seminars in Cell & Developmental Biology 22: 916–926.

Dumont S , Salmon ED and Mitchison TJ (2012) Deformations within moving kinetochores reveal different sites of active and passive force generation. Science 337: 355–358.

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Scholey JM (2008) Intraflagellar transport motors in cilia: moving along the cell's antenna. Journal of Cell Biology 180: 23–29.

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Sirajuddin M , Rice LM and Vale RD (2014) Regulation of microtubule motors by tubulin isotypes and post‐translational modifications. Nature Cell Biology 16: 335–344.

Wittmann T , Hyman A and Desai A (2001) The spindle: a dynamic assembly of microtubule motors. Nature Cell Biology 3: E28–E34.

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Amos, Linda A(Jul 2015) Tubulin and Microtubules. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000676.pub3]