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Asymmetric Molecular Architecture of the Human γ-Tubulin Ring Complex

The γ-tubulin ring complex (γ-TuRC) is an essential regulator of centrosomal and acentrosomal microtubule formation 1–4. Metazoan γ-TuRCs isolate as ∼2 MDa complexes containing the conserved proteins γ-tubulin, GCP2 and GCP3, as well as the expanded subunits GCP4, GCP5, and GCP6 3,5,6. However, in current structural models, γ-TuRCs assemble solely from subcomplexes of γ-tubulin, GCP2 and GCP3 7. The role of the metazoan-specific subunits in γ-TuRC assembly and architecture are not currently known, due to a lack of high resolution structural data for the native complex. Here, we present a cryo-EM structure of the native human γ-TuRC at 3.8Å resolution. Our reconstruction reveals an asymmetric, single helical-turn and cone-shaped structure built from at least 34 polypeptides. Pseudo-atomic models indicate that GCP4, GCP5 and GCP6 form distinct Y-shaped assemblies that structurally mimic GCP2/GCP3 subcomplexes and are distal to the γ-TuRC “seam”. Evolutionary expansion in metazoan-specific subunits diversifies the γ-TuRC by introducing large (>100,000 Å2) surfaces that could interact with different regulatory factors. We also identify an unanticipated structural bridge that includes an actin-like protein and spans the γ-TuRC lumen. Despite its asymmetric composition and architecture, the human γ-TuRC arranges γ-tubulins into a helical geometry poised to nucleate microtubules. The observed compositional complexity of the γ-TuRC could self-regulate its assembly into a cone-shaped structure to control microtubule formation across diverse contexts, e.g. within biological condensates 8 or alongside existing filaments 9.