Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain

Raimond B.G. Ravelli, Benoît Gigant, Patrick A. Curmi, Isabelle Jourdain, Sylvie Lachkar, André Sobel and Marcel Knossow ()
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Raimond B.G. Ravelli: European Molecular Biology Laboratory (EMBL), Grenoble Outstation
Benoît Gigant: Centre National de la Recherche Scientifique
Patrick A. Curmi: U440 INSERM/UPMC, Institut du Fer à Moulin
Isabelle Jourdain: U440 INSERM/UPMC, Institut du Fer à Moulin
Sylvie Lachkar: U440 INSERM/UPMC, Institut du Fer à Moulin
André Sobel: U440 INSERM/UPMC, Institut du Fer à Moulin
Marcel Knossow: Centre National de la Recherche Scientifique

Nature, 2004, vol. 428, issue 6979, 198-202

Abstract: Abstract Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine1 and stathmin family proteins2,3. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 Å resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments4 shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin–colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.

Date: 2004
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DOI: 10.1038/nature02393

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