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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Structural Biology

Background:

  • Faithful chromosome segregation relies on kinetochore attachments to the mitotic spindle.
  • The outer kinetochore KMN network, comprising KNL1C, MIS12C, and NDC80C, connects the inner kinetochore (CCAN) to microtubules.

Purpose of the Study:

  • To determine the high-resolution cryo-electron microscopy (cryo-EM) structure of the human KMN network.
  • To investigate the auto-inhibition mechanism of the MIS12C complex and its regulation.

Main Methods:

  • High-resolution cryo-electron microscopy (cryo-EM) to determine the structure of the human KMN network.
  • Biochemical analysis to study the interaction between MIS12C and CCAN.
  • Site-directed mutagenesis to investigate the role of specific phosphorylation sites.

Main Results:

  • The study revealed an intricate KMN network assembly with MIS12C mediating rigid interfaces with NDC80C and KNL1C.
  • Unphosphorylated MIS12C was found to be in an auto-inhibited state, preventing CCAN interaction.
  • Phosphorylation of Dsn1 subunits (Ser100, Ser109) by Aurora B kinase stabilizes this auto-inhibition.

Conclusions:

  • The structure elucidates the molecular basis of KMN network assembly and its interaction with CCAN.
  • Phosphorylation of MIS12C by Aurora B kinase is crucial for relieving auto-inhibition.
  • This regulation ensures outer kinetochore assembly is restricted to functional centromeres during cell division.