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Characterization of new protein families

Nucleation and organization of microtubules by γ-tubulin complexes

γ-tubulin complex proteins (GCPs) are found in all eukaryotic species, where they form multiprotein complexes with γ-tubulin, bringing the latter into a nucleation-competent configuration thereby insuring microtubule nucleation and mitotic spindle formation.

Five different GCPs are found in human cells and we have determined the crystal structure of the smallest of them (GCP4) and shown that (i) it represents the prototype of all GCPs and (ii) it interacts with γ-tubulin through its C-terminal domain (Nat Struct Mol Biol 2011).

In addition, combination of the GCP4 structure with electron microscopic data obtained on a γ-tubulin complex revealed protein-protein interactions and conformational changes regulating nucleation activity and has allowed us to suggest a new model of microtubule nucleation (Nat Rev Mol Cell Biol 2011).

These structural data pave the way for the design of small molecules capable of inhibiting the formation of complexes between GCPs and γ-tubulin, thereby blocking cell division.

 

Our initial studies indicate that the formation of the protein-protein interface within GCP4/γ-tubulin complex is accompanied by the creation of a pocket which can be targeted by small molecules (PLoS One 2013).

 

 

 

 

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  • Cala, O., Remy, M.H., Guillet, V., Merdes, A., Mourey, L., Milon, A. & Czaplicki, G. (2013). Virtual and biophysical screening targeting the gamma-tubulin complex – A new target for the inhibition of microtubule nucleation. PLoS One 8:e63908
  • Guillet, V., Knibiehler, M., Gregory-Pauron, L., Remy, M.-H., Chemin, C., Raynaud-Messina, B., Bon, C., Kollman, J.M., Agard, D.A., Merdes, A. & Mourey, L. (2011). The crystal structure of gamma-tubulin complex protein GCP4 provides insight into microtubule nucleation. Nat Struct Mol Biol 18:915-19
  • Kollman, J.M., Merdes, A., Mourey, L. & Agard, D.A. (2011). Microtubule nucleation by gamma-tubulin complexes. Nat Rev Mol Cell Biol 12:709-21