Tubulin

Tubulin
kif1a head-microtubule complex structure in atp-form
Identifiers
Symbol	Tubulin
Pfam	PF00091
Pfam clan	CL0442
InterPro	IPR003008
PROSITE	PDOC00201
SCOP	1tub
SUPERFAMILY	1tub
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Tubulin (tubul- + -in) in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoskeleton.^[1] Microtubules function in many essential cellular processes, including mitosis. Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division.

Tubulin was long thought to be specific to eukaryotes. More recently, however, several prokaryotic proteins have been shown to be related to tubulin.^[2][3][4][5]

Characterization

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

This GTPase protein domain is found in all eukaryotic tubulin chains,^[6] as well as the bacterial protein TubZ,^[5] the archaeal protein CetZ,^[7] and the FtsZ protein family widespread in Bacteria and Archaea.^[2][8]

Function

Comparison of the architectures of a 5-protofilament bacterial microtubule (left; BtubA in dark blue; BtubB in light-blue) and a 13-protofilament eukaryotic microtubule (right; α-tubulin in white; β-tubulin in black). Seams and start-helices are indicated in green and red, respectively.^[9]

Microtubules

α- and β-tubulin 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-tubulin. These subunits are slightly acidic with an isoelectric point between 5.2 and 5.8.^[10] Each has a molecular weight of approximately 50,000 Daltons.^[11]

To form microtubules, the dimers of α- and β-tubulin bind to GTP and assemble onto the (+) ends of microtubules while in the GTP-bound state.^[12] The β-tubulin subunit is exposed on the plus end of the microtubule while the α-tubulin subunit is exposed on the minus end. After the dimer is incorporated into the microtubule, the molecule of GTP bound to the β-tubulin subunit eventually hydrolyzes into GDP through inter-dimer contacts along the microtubule protofilament.^[13] Whether the β-tubulin member of the tubulin dimer is bound to GTP or GDP influences the stability of the dimer in the microtubule. Dimers bound to GTP tend to assemble into microtubules, while dimers bound to GDP tend to fall apart; thus, this GTP cycle is essential for the dynamic instability of the microtubule.

Bacterial Microtubules

Homologs of α- and β-tubulin have been identified in the Prosthecobacter genus of bacteria.^[3] They are designated BtubA and BtubB to identify them as bacterial tubulins. Both exhibit homology to both α- and β-tubulin.^[14] While structurally highly similar to eukaryotic tubulins, they have several unique features, including chaperone-free folding and weak dimerization.^[15] Electron cryomicroscopy showed that BtubA/B form microtubules in vivo, and that these microtubules comprise only five protofilaments, in contrast to eukaryotic microtubules, which usually contain 13.^[16]

Prokaryotic Division

FtsZ is found in nearly all Bacteria and Archaea, where it functions in cell division, localizing to a ring in the middle of the dividing cell and recruiting other components of the divisome, the group of proteins that together constrict the cell envelope to pinch off the cell, yielding two daughter cells. FtsZ can polymerize into tubes, sheets, and rings in vitro, and forms dynamic filaments in vivo.

TubZ functions in segregating low copy-number plasmids during bacterial cell division. The protein forms a structure unusual for a tubulin homolog; two helical filaments wrap around one another.^[17] This may reflect an optimal structure for this role since the unrelated plasmid-partitioning protein ParM exhibits a similar structure.^[18]

Cell Shape

CetZ functions in cell shape changes in pleomorphic Haloarchaea. In Haloferax volcanii, CetZ forms dynamic cytoskeletal structures required for differentiation from a plate-shaped cell form into a rod-shaped form that exhibits swimming motility.^[7]

Types

Eukaryotic

The tubulin superfamily contains six families of tubulins (alpha-, beta-, gamma-, delta-, epsilon and zeta-tubulins).^[19]

α-Tubulin

Human α-tubulin subtypes include:

β-Tubulin

β-tubulin in Tetrahymena sp.

All drugs that are known to bind to human tubulin bind to β-tubulin.^[20] These include paclitaxel, colchicine, and the vinca alkaloids, each of which have a distinct binding site on β-tubulin.^[20]

Class III β-tubulin is a microtubule element expressed exclusively in neurons,^[21] and is a popular identifier specific for neurons in nervous tissue. It binds colchicine much more slowly than other isotypes of β-tubulin.^[22]

β1-tubulin, sometimes called class VI β-tubulin,^[23] is the most divergent at the amino acid sequence level.^[24] It is expressed exclusively in megakaryocytes and platelets in humans and appears to play an important role in the formation of platelets.^[24]

Katanin is a protein complex that severs microtubules at β-tubulin subunits, and is necessary for rapid microtubule transport in neurons and in higher plants.^[25]

Human β-tubulins subtypes include:

γ-Tubulin

γ-Tubulin, another member of the tubulin family, is important in the nucleation and polar orientation of microtubules. It is found primarily in centrosomes and spindle pole bodies, since these are the areas of most abundant microtubule nucleation. In these organelles, several γ-tubulin and other protein molecules are found in complexes known as γ-tubulin ring complexes (γ-TuRCs), which chemically mimic the (+) end of a microtubule and thus allow microtubules to bind. γ-tubulin also has been isolated as a dimer and as a part of a γ-tubulin small complex (γTuSC), intermediate in size between the dimer and the γTuRC. γ-tubulin is the best understood mechanism of microtubule nucleation, but certain studies have indicated that certain cells may be able to adapt to its absence, as indicated by mutation and RNAi studies that have inhibited its correct expression.

Human γ-tubulin subtypes include:

• TUBG1
• TUBG2

Members of the γ-tubulin ring complex:

δ and ε-Tubulin

Delta (δ) and epsilon (ε) tubulin have been found to localize at centrioles and may play a role in forming the mitotic spindle during mitosis, though neither is as well-studied as the α- and β- forms.

Human δ- and ε-tubulin subtypes include:

• δ-tubulin
  • TUBD1
• ε-tubulin
  • TUBE1

ζ-Tubulin

Zeta-tubulin is present only in kinetoplastid protozoa.^[19]

Prokaryotic

BtubA/B

BtubA/B are found in some bacterial species in the Verrucomicrobial genus Prosthecobacter.^[3] Their evolutionary relationship to eukaryotic tubulins is unclear, although they may have descended from a eukaryotic lineage by lateral gene transfer.^[15][26]

FtsZ

Nearly all bacterial and archaeal cells use FtsZ to divide.^[27] It was the first prokaryotic cytoskeletal protein identified.

TubZ

TubZ was identified in Bacillus thuringiensis as essential for plasmid maintenance.^[5]

CetZ

CetZ is found in the euryarchaeal clades of Methanomicrobia and Halobacteria, where it functions in cell shape differentiation.^[7]

Pharmacology

Tubulins are targets for anticancer drugs like Taxol, Tesetaxel and the "Vinca alkaloid" drugs such as vinblastine and vincristine. The anti-gout agent colchicine binds to tubulin and inhibits microtubule formation, arresting neutrophil motility and decreasing inflammation. The anti-fungal drug Griseofulvin targets microtubule formation and has applications in cancer treatment.

Post-translational modifications

When incorporated into microtubules, tubulin accumulates a number of post-translational modifications, many of which are unique to these proteins. These modifications include detyrosination, acetylation, polyglutamylation, polyglycylation, phosphorylation, ubiquitination, sumoylation, and palmitoylation.

See also

References

External links

• Tubulin at the US National Library of Medicine Medical Subject Headings (MeSH)
• EC 3.6.5.6
• protocol for purification of tubulin from bovine brain