Microtubule Nucleation by Single Human γTuRC in a Partly Open Asymmetric Conformation
Consolati, T.; Locke, J.; Roostalu, J.; Asthana, J.; Lim, W. M.; Gannon, J.; Martino, F.; Costa, A.; Surrey, T.
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The {gamma}-tubulin ring complex ({gamma}TuRC) is the major microtubule nucleator in cells. However, the mechanism of its regulation is not understood. Here, we purified human {gamma}TuRC and quantitatively characterized its nucleation properties in a TIRF microscopy-based real-time nucleation assay. We find that microtubule nucleation by {gamma}TuRC is kinetically inhibited compared to microtubule elongation. Determining the cryo-EM structure of {gamma}TuRC at 4 [A] resolution reveals an asymmetric conformation with only part of the complex in a closed conformation matching the microtubule geometry. Several factors stabilise the closed conformation. One is actin in the core of the complex and others, likely MZT1 or MZT2, line the outer perimeter of the closed part of {gamma}TuRC. The opposed side of {gamma}TuRC is in an open, nucleation-incompetent conformation, leading to a structural asymmetry, explaining the kinetic inhibition of nucleation by human {gamma}TuRC. Our data suggest possible regulatory mechanisms for microtubule nucleation by {gamma}TuRC closure.
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