Distinct Organization and Regulation of the Outer Kinetochore KMN Network Downstream of CENP-C and CENP-T
Name
Cheeseman_Distinct organization.pdf
Size
1.33 MB
Format
Adobe PDF
Checksum (MD5)
ef9aee39018da2bd33d142568cd07c5c
Author(s)
Rago, Florencia
Gascoigne, Karen E.
Cheeseman, Iain M
Date Issued
February 2015
Journal
Current Biology
Publisher
Elsevier
Citation
Rago, Florencia, Karen E. Gascoigne, and Iain M. Cheeseman. “Distinct Organization and Regulation of the Outer Kinetochore KMN Network Downstream of CENP-C and CENP-T.” Current Biology 25.5 (2015): 671–677.
Version
Author's final manuscript
Abstract
The kinetochore provides a vital connection between chromosomes and spindle microtubules [1 and 2]. Defining the molecular architecture of the core kinetochore components is critical for understanding the mechanisms by which the kinetochore directs chromosome segregation. The KNL1/Mis12 complex/Ndc80 complex (KMN) network acts as the primary microtubule-binding interface at kinetochores [3] and provides a platform to recruit regulatory proteins [4]. Recent work found that the inner kinetochore components CENP-C and CENP-T act in parallel to recruit the KMN network to kinetochores [5, 6, 7 and 8]. However, due to the presence of these dual pathways, it has not been possible to distinguish differences in the nature of kinetochore assembly downstream of CENP-C or CENP-T. Here, we separated these pathways by targeting CENP-C and CENP-T independently to an ectopic chromosomal locus in human cells. Our work reveals that the organization of the KMN network components downstream of CENP-C and CENP-T is distinct. CENP-C recruits the Ndc80 complex through its interactions with KNL1 and the Mis12 complex. In contrast, CENP-T directly interacts with Ndc80, which in turn promotes KNL1/Mis12 complex recruitment through a separate region on CENP-T, resulting in functional relationships for KMN network localization that are inverted relative to the CENP-C pathway. We also find that distinct regulatory paradigms control the assembly of these pathways, with Aurora B kinase promoting KMN network recruitment to CENP-C and cyclin-dependent kinase (CDK) regulating KMN network recruitment to CENP-T. This work reveals unexpected complexity for the architecture and regulation of the core components of the kinetochore-microtubule interface.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.cub.2015.01.059
