Accurate phosphoregulation of kinetochore–microtubule affinity requires unconstrained molecular interactions

Zaytsev, Anatoly V.; Sundin, Lynsie J.R.; DeLuca, Keith F.; Grishchuk, Ekaterina L.; DeLuca, Jennifer G.

doi:10.1083/jcb.201312107

Cited by 106 publications

(173 citation statements)

References 48 publications

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“…Because the oscillation amplitude is A ∼ vτ, the enhanced kinetochore speeds lead to larger oscillations and decreased kinetochore alignment (Fig. 4 B and C), consistent with previous in vivo results (10,18). Our finding is also consistent with experiments showing decreased oscillation speed and amplitude when phosphorylation by Aurora B is suppressed (16).…”

Section: Discussionsupporting

confidence: 82%

“…Incorrect attachments-such as syntelic attachment of both kinetochores to the same pole-must be corrected (13)(14)(15)(16)(17). Tension may cue this process because bioriented kinetochore pairs are under tension while syntelically attached kinetochores are not (7,9,15,17,18). Error correction is also mediated by Aurora B kinase phosphorylating MT-binding kinetochore proteins (13)(14)(15)(16)(17)(19)(20)(21).…”

mentioning

confidence: 99%

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Minimal model for collective kinetochore–microtubule dynamics

Banigan

Chiou

Ballister

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Chromosome segregation during cell division depends on interactions of kinetochores with dynamic microtubules (MTs). In many eukaryotes, each kinetochore binds multiple MTs, but the collective behavior of these coupled MTs is not well understood. We present a minimal model for collective kinetochore–MT dynamics, based on in vitro measurements of individual MTs and their dependence on force and kinetochore phosphorylation by Aurora B kinase. For a system of multiple MTs connected to the same kinetochore, the force–velocity relation has a bistable regime with two possible steady-state velocities: rapid shortening or slow growth. Bistability, combined with the difference between the growing and shrinking speeds, leads to center-of-mass and breathing oscillations in bioriented sister kinetochore pairs. Kinetochore phosphorylation shifts the bistable region to higher tensions, so that only the rapidly shortening state is stable at low tension. Thus, phosphorylation leads to error correction for kinetochores that are not under tension. We challenged the model with new experiments, using chemically induced dimerization to enhance Aurora B activity at metaphase kinetochores. The model suggests that the experimentally observed disordering of the metaphase plate occurs because phosphorylation increases kinetochore speeds by biasing MTs to shrink. Our minimal model qualitatively captures certain characteristic features of kinetochore dynamics, illustrates how biochemical signals such as phosphorylation may regulate the dynamics, and provides a theoretical framework for understanding other factors that control the dynamics in vivo.

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Section: Discussionsupporting

confidence: 82%

mentioning

confidence: 99%

Minimal model for collective kinetochore–microtubule dynamics

Banigan

Chiou

Ballister

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…7, 2018; with 9A-Hec1, which cannot be phosphorylated on the nine mutated target sites, we no longer observed a 1 significant correlation between NDC80 FRET fraction and K-K distance (p=0.20) ( Figure 5A). 9A-Hec1-2 expressing cells displayed significantly larger K-K distance than unperturbed cells (1.36 µm ± 0.21 µm, 3 SD, p < 10 -30 ) (Figure 5B), consistent with previous studies (Tauchman et al, 2015, Zaytsev et al, 2014.…”

Section: Ndc80-kmt Bindingsupporting

confidence: 81%

“…The NDC80 binding fraction (converted from NDC80 FRET 7 fraction) decreased with the number of phospho-mimicking mutations, from 38%1% with 9A-Hec1 (all 8 nine phosphorylation sites substituted with Ala) to 14%1% with 2D-Hec1 (two sites, S44 and S55, 9 substituted with Asp while the others with Ala) and to 11%1% with 9D-Hec1 (all nine sites substituted 10 with Asp) (meanSEM, Figure 4C). The average NDC80 binding of WT-Hec1 was similar, but slightly 11 higher than 2D-Hec1, consistent with previous results arguing that on average there are zero to two sites 12 phosphorylated per Hec1/Ndc80 protein in prometaphase and metaphase (Zaytsev et al, 2014).…”

supporting

confidence: 79%

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Measuring NDC80 binding reveals the molecular basis of tension-dependent kinetochore-microtubule attachments

Yoo

Choi

Conway

et al. 2018

Preprint

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MAPping the Ndc80 loop in cancer: A possible link between Ndc80/Hec1 overproduction and cancer formation

Tang

Toda

2015

BioEssays

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Mis-regulation (e.g. overproduction) of the human Ndc80/Hec1 outer kinetochore protein has been associated with aneuploidy and tumourigenesis, but the genetic basis and underlying mechanisms of this phenomenon remain poorly understood. Recent studies have identified the ubiquitous Ndc80 internal loop as a protein-protein interaction platform. Binding partners include the Ska complex, the replication licensing factor Cdt1, the Dam1 complex, TACC-TOG microtubule-associated proteins (MAPs) and kinesin motors. We review the field and propose that the overproduction of Ndc80 may unfavourably absorb these interactors through the internal loop domain and lead to a change in the equilibrium of MAPs and motors in the cells. This sequestration will disrupt microtubule dynamics and the proper segregation of chromosomes in mitosis, leading to aneuploid formation. Further investigation of Ndc80 internal loop-MAPs interactions will bring new insights into their roles in kinetochore-microtubule attachment and tumourigenesis.

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Accurate phosphoregulation of kinetochore–microtubule affinity requires unconstrained molecular interactions

Abstract: Accurate regulation of kinetochore–microtubule affinity is driven by incremental phosphorylation of an NDC80 molecular “lawn,” in which NDC80–microtubule bonds reorganize dynamically in response to the number and stability of microtubule attachments.

Cited by 106 publications

References 48 publications

Minimal model for collective kinetochore–microtubule dynamics

Minimal model for collective kinetochore–microtubule dynamics

Measuring NDC80 binding reveals the molecular basis of tension-dependent kinetochore-microtubule attachments

MAPping the Ndc80 loop in cancer: A possible link between Ndc80/Hec1 overproduction and cancer formation

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