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Distinct Organization and Regulation of the Outer Kinetochore KMN Network Downstream of CENP-C and CENP-T

Authors :
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Cheeseman, Iain M
Rago, Florencia
Gascoigne, Karen E.
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Cheeseman, Iain M
Rago, Florencia
Gascoigne, Karen E.
Source :
PMC
Publication Year :
2017

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.<br />Leukemia & Lymphoma Society of America (Scholar Award)<br />National Institutes of Health (U.S.) (National Institute of General Medical Sciences (U.S.). Grant GM088313)<br />American Cancer Society (Research Scholar Grant 121776)

Details

Database :
OAIster
Journal :
PMC
Notes :
application/pdf, en_US
Publication Type :
Electronic Resource
Accession number :
edsoai.on1141890617
Document Type :
Electronic Resource