KNL1Mis12Ndc80

Knl1Mis12Ndc80, commonly referred to as the KMN network, is a conserved core assembly at the outer kinetochore that connects centromeric chromatin to spindle microtubules during mitosis. It is comprised of three interdependent subcomplexes: the KNL1 complex, the MIS12 complex, and the NDC80 complex. The MIS12 complex includes subunits such as MIS12, DSN1, NSL1, and NNF1; the NDC80 complex contains NDC80 (Hec1), NUF2, SPC24, and SPC25; and the KNL1 complex centers on the KNL1 protein, which serves as a scaffold integrating kinetochore components.

Function and organization

The KMN network forms the principal microtubule-binding interface at the kinetochore, enabling stable attachment of spindle microtubules to kinetochores during chromosome alignment and segregation. The MIS12 complex serves as a bridge linking the KNL1 scaffold to the NDC80 microtubule-binding complex, stabilizing outer kinetochore architecture and coordinating microtubule engagement with inner kinetochore signals. The NDC80 complex directly binds microtubules, while KNL1 coordinates interactions with other kinetochore proteins and contributes to the recruitment of spindle assembly checkpoint components.

Regulation and significance

Attachment stability and checkpoint signaling are regulated by phosphorylation events (notably by kinases such as Mps1 and Aurora B), which modulate KMN interactions to ensure proper chromosome biorientation and the spindle assembly checkpoint. The KMN network is essential for accurate chromosome segregation, and its dysfunction can lead to aneuploidy with implications in development and disease, including cancer.

Evolution and study

The KMN network is evolutionarily conserved from yeasts to humans and has been interrogated through structural, biophysical, and cell biological approaches, including cryo-electron microscopy and fluorescence imaging, to elucidate its architecture and regulatory mechanisms.