Tubulin: Definition, Characteristics, Microtubules, Types and Pharmacology

In molecular biology, it may refer to the tubulin protein superfamily of globular proteins, or to one of the member proteins of that superfamily.

The α and β tubulins polymerize into microtubules, a major component of the eukaryotic cytoskeleton. Microtubules function in many essential cellular processes, including mitosis.

Tubulin-binding drugs kill cancer cells by inhibiting microtubule dynamics, which are necessary for DNA segregation and thus cell division.

In eukaryotes there are six members of the tubulin superfamily, although not all are present in all species. Both α and β tubulins have a mass of around 50 kDa and are therefore in a similar range compared to actin at 42 kDa.

In contrast, tubulin polymers (microtubules) tend to be much larger than actin filaments due to their cylindrical nature.

Tubulin was long thought to be specific to eukaryotes. However, several prokaryotic proteins have been shown to be related to tubulin.

Characterization

Tubulin is characterized by the evolutionarily conserved Tubulin / FtsZ family, domain of the GTPase protein.

This domain of the GTPase protein is found in all eukaryotic tubulin chains, as well as the bacterial Tubz protein, the archaeal CETZ protein, and FtsZ, a family of proteins that are widespread in bacteria.

Microtubules

The α and β tubulins polymerize into dynamic microtubules. In eukaryotes, microtubules are one of the major components of the cytoskeleton and function in many processes, including structural support, intracellular transport, and DNA segregation.

Microtubules are assembled from dimers of α and β tubulins. These subunits are slightly acidic with an isoelectric point between 5.2 and 5.8. Each has a molecular weight of approximately 50 kDa.

To form microtubules, dimers of α and β tubulins bind to GTP and assemble at the (+) ends of microtubules in the GTP-bound state.

The β-tubulin subunit is exposed at the positive end of microtubules while the α-tubulin subunit is exposed at the negative end.

After the dimer is incorporated into the microtubule, the GTP molecule attached to the β-tubulin subunit is finally hydrolyzed into GDP by interdimeric contacts along the protofilament of the microtubules.

Whether the β-tubulin member of the tubulin dimer binds to GTP or GDP influences the stability of the dimer in the microtubule. GTP-bound dimers tend to assemble into microtubules, while GDP-bound dimers tend to crumble; therefore, this GTP cycle is essential for dynamic microtubule instability.

Bacterial microtubules

Homologues of α and β tubulins have been identified in the genus of bacteria Prosthecobacter. They are designated BtubA and BtubB to identify them as bacterial tubulins.

Both exhibit homology with both α and β-tubulin. Although they are structurally very similar to eukaryotic tubulins, they have several unique characteristics, including chaperone-free folding and weak dimerization.

Electron cryomicroscopy showed that BtubA / B forms microtubules “in vivo”, and suggested that these microtubules comprise only five protofilaments, in contrast to eukaryotic microtubules, which generally contain 13.

Types

Eukaryotic

The tubulin superfamily contains six families of tubulins (alpha-, beta-, gamma-, delta-, epsilon, and zeta-tubulins).

α-tubulin

Human α-tubulin subtypes include:

  • TUBA1A.
  • TUBA1B.
  • TUBA1C.
  • TUBA3C.
  • TUBA3D.
  • TUBA3E.
  • TUBA4A.
  • TUBA8.

β-tubulin

All drugs that are known to bind human tubulin bind to β-tubulin. These include paclitaxel, colchicine, and vinca alkaloids, each of which has a different binding site on β-tubulin.

Class III β-tubulin is a microtubule element expressed exclusively in neurons, and is a popular identifier specific for neurons in nervous tissue.

Katanin is a protein complex that cuts microtubules into the β-tubulin subunits, and is necessary for the rapid transport of microtubules in neurons and higher plants.

Human β-tubulin subtypes include:

  • TUBB.
  • TUBB1.
  • TUBB2A.
  • TUBB2B.
  • TUBB2C.
  • TUBB3.
  • TUBB4.
  • TUBB4Q.
  • TUBB6.

γ-Tubulin

Γ-Tubulin, another member of the tubulin family, is important in the nucleation and polar orientation of microtubules. It is found mainly in centrosomes and spindle-shaped pole bodies, as these are the most abundant nucleation areas of microtubules.

Human γ-tubulin subtypes include:

  • TUBG1.
  • TUBG2.

Members of the γ-tubulin ring complex:

  • TUBGCP2.
  • TUBGCP3.
  • TUBGCP4.
  • TUBGCP5.
  • TUBGCP6.

δ y ε-Tubulina

Delta (δ) and epsilon (ε) tubulin have been found to localize to centrioles and may play a role in centriole structure and function, although neither is as well studied as the α and β forms.

The human δ- and ε-tubulin genes include:

δ-tubulin

  • TUBD1.

ε-tubulin

  • TUBE1.

ζ-Tubulin

Zeta-tubulin is present in many eukaryotes, but is lacking in others, including placental mammals. It has been shown to be associated with the basal foot structure of the centrioles in multiciliated epithelial cells.

Prokaryotic

BtubA / B

BtubA / B are found in some bacterial species in the genus Verrucomicrobial Prosthecobacter. Their evolutionary relationship with eukaryotic tubulins is unclear, although they may have descended from a eukaryotic lineage by lateral gene transfer.

FtsZ

Almost all bacterial and archaea cells use FtsZ to divide. It was the first identified prokaryotic cytoskeletal protein.

TubZ

TubZ was identified in Bacillus thuringiensis as essential for plasmid maintenance.

CetZ

CetZ is found in the euryarchaeal clades of Methanomicrobia and Halobacteria, where it functions in cell shape differentiation.

Pharmacology

Tubulins are targets for anticancer drugs such as the vinca alkaloids vinblastine and vincristine, and paclitaxel. The anti-gout agent colchicine binds to tubulin and inhibits microtubule formation, stopping neutrophil motility and decreasing inflammation.

The antifungal drug griseofulvin targets microtubule formation and has applications in the treatment of cancer.