Structure of the human inner kinetochore CCAN complex and its significance for human centromere organization
Marion E.Pesenti 1, 4 Tobias Raisch 2, 4 Duccio Conti 1, 5 Kai Walstein 1, 5 Ingrid Hoffmann 1 Dorothee Vogt 1 Daniel Prumbaum 2 Ingrid R.Vetter 1 Stefan Raunser 2 Andrea Musacchio 1, 3, 6
https://doi.org/10.1016/j.molcel.2022.04.027
Under a Creative Commons license
Highlights
• A cryo-EM structure of the CCAN is reported
• The structure rationalizes relative positions and roles of the 16 CCAN subunits
• The CCAN core is shown to prefer naked DNA to CENP-A nucleosomes
• Several possible models of organization of centromeric chromatin are discussed
Summary
Centromeres are specialized chromosome loci that seed the kinetochore, a large protein complex that effects chromosome segregation. A 16-subunit complex, the constitutive centromere associated network (CCAN), connects between the specialized centromeric chromatin, marked by the histone H3 variant CENP-A, and the spindle-binding moiety of the kinetochore. Here, we report a cryo-electron microscopy structure of human CCAN. We highlight unique features such as the pseudo GTPase CENP-M and report how a crucial CENP-C motif binds the CENP-LN complex. The CCAN structure has implications for the mechanism of specific recognition of the CENP-A nucleosome. A model consistent with our structure depicts the CENP-C-bound nucleosome as connected to the CCAN through extended, flexible regions of CENP-C. An alternative model identifies both CENP-C and CENP-N as specificity determinants but requires CENP-N to bind CENP-A in a mode distinct from the classical nucleosome octamer.
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