Tubulin and FtsZ Superfamily of Protein Assembly Machines


Eukaryotic αβ‐tubulin and bacterial FtsZ self‐assemble into dynamic cytoskeletal polymers, microtubules or filaments, which are essential for chromosome segregation or bacterial cell division, respectively. Both share homologous core structures with guanosine‐5'‐triphosphate (GTP)‐binding and GTPase‐activating domains joined by a central helix, and form similar protofilaments with 4 nm spaced subunits along them. During assembly, the GTPase‐activating domain of one subunit associates with the GTP binding domain of the preceding subunit, completing the active site. GTP hydrolysis triggers disassembly, which is coupled to free subunits switching into inactive conformation. Microtubule dynamics is inhibited by anticancer drugs binding near tubulin assembly interfaces. FtsZ is a target for new antibiotics discovery; several bacterial division inhibitors bind between FtsZ domains or at its GTP site. Other proteins in this superfamily include: gamma‐tubulin that is essential for microtubule organisation; bacterial tubulin, a primitive structural homologue; and recently discovered TubZ, distant homologue employed by plasmids and phages for deoxyribonucleic acid positioning.

Key Concepts:

  • Tubulin superfamily proteins share a common fold within two domains that is different from other GTPases.

  • They assemble into microtubules and other different types of dynamic cytoskeletal filaments.

  • GTP hydrolysis is activated upon assembly and triggers disassembly.

  • Tubulin homologues spread among most organisms, where they are central to essential functions including DNA segregation or cell division.

  • They have important biomedical implications. Several effective antitumor drugs work by impairing microtubule dynamics. FtsZ is a target for new antibiotics.

Keywords: protein self‐assembly; GTPases; microtubules; anticancer drugs; bacterial cell division; antibiotics

Figure 1.

Evolution scheme and structural homology of the tubulin superfamily of proteins. Top, two hypothetical independent proteins, a GTP binding protein (green, nucleotide in yellow) and a GTPase complementing protein (orange) fused into a single protein with two domains, which had to assemble for GTP hydrolysis activation. Middle, the ancestor protein spread had independently evolved into the tubulin, FtsZ and TubZ families of proteins. The presence of tubulin genes in two Nitrosoarchaeum genomes (named artubulin) suggests an archaeal origin of eukaryotic tubulins (Yutin and Koonin, ). Bacterial tubulin BtubA/B encoded by several Prosthecobacter species is thought to have evolved following horizontal transfer of primitive tubulin genes to an ancestor of this group of bacteria (see main text). Bottom, the structures of the extant proteins in the tubulin superfamily share a conserved fold of two domains (green, GTP binding; orange, GTPase activating) joined by a core helix (dark grey). Significant differences include surface loops, the C‐terminal structural elements at the left‐back of each view and the N‐termini (both marked light grey). The protein structural files were taken from the Protein Data Bank (PDB) and displayed as ribbons with PYMOL. The PDB entries used are: gamma‐tubulin, 1Z5W; alphabeta‐tubulin, 1JFF; bacterial tubulin, 2BTQ; FtsZ, 1FSZ; TubZ and 3M8K.

Figure 2.

Assemblies and subcellular structures formed by the tubulin superfamily proteins. Top, negative stain electron microscopy images of the polymers assembled from these proteins. Magnification bars indicate 100 nm. Medium resolution structural models shown coloured are: gamma‐tubulin ring complexes (reproduced from Kollman et al., . © Nature Publishing Group); microtubules (reproduced from Electron Microscopy Data Bank, EMD‐2004, Maurer SP et al., ) and TubZ 2, 3, and 4‐stranded filaments (reproduced from the Electron Microscopy Data Bank, EMD‐ 5762, 5763 and 5783; Montabana and Agard, ; Zehr et al., ). BtubA/B polymers shown are filaments (reproduced from Schlieper et al., . © The National Academy of Sciences) and tubes (electron cryo‐tomography and model; reproduced from Pilhofer et al., ). Bottom, functions and characteristic sucellular structures formed by each protein, using light microscopy or cryo‐tomography (BtubA/B, reproduced from Pilhofer et al., ). Centrosomes are stained with antibodies to gamma‐tubulin (yellow), cytoplasmic and spindle microtubules are directly imaged here with a green fluorescent derivative of the antitumor drug taxol (see method in Barasoain et al., ). DNA is stained blue . Bacterial Z‐rings are visualized green with FtsZ fused to green fluorescent protein (GFP). Filaments formed by TubZ‐GFP expressed in Bacillus cells (reproduced with permission from Larsen et al., . © Cold Spring Harbor Laboratory Press).

Figure 3.

(a) Scheme of αβ‐tubulin assembly and microtubule dynamic instability. Reproduced with permission from Akhmanova and Steinmetz () © Nature Publishing Group. (b) Straight and curved conformations of the αβ‐tubulin heterodimer; the straight structure on the left was obtained by electron crystallography of tubulin sheets with bound taxol (from PDB entry 1JFF). The curved structure shown was determined by x‐ray crystallography of αβ‐tubulin in complex with a plus end capping DARPIN domain (from PDB 4DRX). (c) Localisation of drug binding sites, shown on the complex of two curved tubulin heterodimers with the stathmin‐like domain of protein RB3 [RB3‐SLD, light blue]. We only show one ligand for each characterised binding pocket: epotilone (orange) and peroluside (purple) (from PDB 404L), colchicine (red) and vinblastine (blue) (from PDB 1Z2B) and PM060184 (green blue) (from PDB 4TV9), which shares a new binding site with maytansine (Prota et al., ). As a reference for orientation we highlight the location of the nucleotide at the N‐domain.

Figure 4.

Model of γ‐tubulin complexes and microtubule attachment. (a) In γTuSC small complexes, associated proteins (green, blue) act as scaffolds for two γ‐tubulin molecules (yellow). (b) The ‘lock washer’ structure of γTubRC ring complexes made of several laterally interacting γTuSC. In this complex, γ‐tubulin molecules are exposed for interaction with microtubules. (c) The γTuRC ring complex functions as a template nucleating the microtubule minus‐end. Specific protein attachment factors are required for the attachment of these complexes to the MTOC or to other microtubules. Reproduced with permission from Kollman et al. () © Nature Publishing Group.

Figure 5.

FtsZ filaments localisation, dynamics and structural assembly switch. (a) The Z‐ring localises at cell division site after the replication and segregation of the bacterial chromosome and it is made up of multiple FtsZ protofilaments. (b) Scheme of the assembly‐disassembly cycle of purified FtsZ. FtsZ protofilaments remain relatively straight when GTP (T) is bound and curve upon hydrolysis to GDP (D). (c) A straight filament (blue) observed in the crystal packing of S. aureus FtsZ (PDB 3VO8). (d) The putative FtsZ assembly switch from a close structure when unassembled (salmon, PDB 2VAM) to an open structure in the protofilament (blue, PDB 3VO8) involves an opening movement of the C‐terminal domain and a downshift movement of the central helix H7 (see main text).

Figure 6.

(a) Scheme of segregation of newly replicated extrachromosomal DNAs that are attached to mobile TubZ filaments through a DNA adaptor protein in type III segregation systems (data from Ni et al., ). (b) Scheme of DNA positioning DNA by TubZ homologue filaments at the middle of the cell during encapsidation of phage 201φ2‐1 (data from Kraemer et al., ).



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Oliva, María A, and Andreu, José M(Sep 2014) Tubulin and FtsZ Superfamily of Protein Assembly Machines. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025586]