Successive Kinesin-5 Microtubule Crosslinking and Sliding Promote Fast, Irreversible Formation of a Stereotyped Bipolar Spindle

Leary, Allen; Sim, Shannon; Nazarova, Elena; Shulist, Kristian; Genthial, Rachel; Yang, Shun Kai; Bui, Khanh Huy; François, Paul; Vogel, Jackie

doi:10.1016/j.cub.2019.09.030

Cited by 17 publications

(17 citation statements)

References 70 publications

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“…8 ). This is consistent with recent studies demonstrating that the initial step in the monopolar-to-bipolar transition is driven by Kinesin-5–based cross-linking ( Leary et al, 2019 ). Our results indicate, however, that despite the presence of Kinesin-5, plus-end targeted Kinesin-14 and Ase1 are critically required for the maturation of the nascent metaphase spindle into a properly organized scaffold for kinetochores to bi-orient.…”

Section: Discussionsupporting

confidence: 93%

“…Our results show, however, that these functions of Cik1-Kar3 are accomplished as a complex with Bim1 at the microtubule plus end, suggesting that the type of antiparallel zippering proposed by Gardner and colleagues (Hepperla et al, 2014), which would include Bim1-independent translocation along microtubules, may provide only a secondary contribution. We rather favor the idea that parallel bundles generated by Bim1-Cik1-Kar3 from both SPBs serve as optimized binding sites with sufficient overlap for Kinesin-5 motors whose role in early spindle formation was described recently (Leary et al, 2019).…”

Section: Discussionmentioning

confidence: 80%

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The EB1–Kinesin-14 complex is required for efficient metaphase spindle assembly and kinetochore bi-orientation

Kornakov

Möllers

Westermann

2020

Journal of Cell Biology

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Kinesin-14s are conserved molecular motors required for high-fidelity chromosome segregation, but their specific contributions to spindle function have not been fully defined. Here, we show that key functions of budding yeast Kinesin-14 Cik1-Kar3 are accomplished in a complex with Bim1 (yeast EB1). Genetic complementation of mitotic phenotypes identifies a novel KLTF peptide motif in the Cik1 N-terminus. We show that this motif is one element of a tripartite binding interface required to form a high-affinity Bim1–Cik1-Kar3 complex. Lack of Bim1-binding by Cik1-Kar3 delays cells in mitosis and impairs microtubule bundle organization and dynamics. Conversely, constitutive targeting of Cik1-Kar3 to microtubule plus ends induces the formation of nuclear microtubule bundles. Cells lacking the Bim1–Cik1-Kar3 complex rely on the conserved microtubule bundler Ase1/PRC1 for metaphase spindle organization, and simultaneous loss of plus-end targeted Kar3 and Ase1 is lethal. Our results reveal the contributions of an EB1–Kinesin-14 complex for spindle formation as a prerequisite for efficient kinetochore clustering and bi-orientation.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 80%

The EB1–Kinesin-14 complex is required for efficient metaphase spindle assembly and kinetochore bi-orientation

Kornakov

Möllers

Westermann

2020

Journal of Cell Biology

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“…Are both inter-CS and CS-cortex interactions necessary? All these spindle types -monopolar (18)(19)(20), bipolar and multipolar -have been observed (5,11,12,21), so what are the necessary and sufficient mechanics for the emergence of the bipolar spindle?…”

Section: Introductionmentioning

confidence: 99%

Mechanics of Multicentrosomal Clustering in Bipolar Mitotic Spindles

Chatterjee

Sarkar

Zhu

et al. 2020

Biophysical Journal

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To segregate chromosomes in mitosis, cells assemble mitotic spindle, a molecular machine with centrosomes at two opposing cell poles and chromosomes at the equator. Microtubules and molecular motors connect the poles to kinetochores, specialized protein assemblies on the centromere regions of the chromosomes. Bipolarity of the spindle is crucial for the proper cell division, and two centrosomes in animal cells naturally become two spindle poles. Cancer cells are often multi-centrosomal, yet they are able to assemble bipolar spindles by clustering centrosomes into two spindle poles. Mechanisms of this clustering are debated. In this study, we computationally screen effective forces between a) centrosomes, b) centrosomes and kinetochores, c) centrosomes and chromosome arms, d) centrosomes and cell cortex, to understand mechanics that determines three-dimensional spindle architecture. To do this, we use stochastic Monte Carlo search for stable mechanical equilibria in effective energy landscape of the spindle. We find that the following conditions have to be met to robustly assemble the bipolar spindle in a multi-centrosomal cell: 1) strengths of centrosomes' attraction to each other and to the cell cortex have to be proportional to each other; 2) strengths of centrosomes' attraction to kinetochores and repulsion from the chromosome arms have to be proportional to each other. We also find that three other spindle configurations emerge if these conditions are not met: a) collapsed, b) monopolar, c) multipolar spindles, and the computational screen reveal mechanical conditions for these abnormal spindles. Running title: Multi-centrosomal clusteringSignificance statement: To segregate chromosomes, cells assemble bipolar mitotic spindle. Multiple mechanical forces generated by microtubules and molecular motors in the spindle govern the spindle architecture, but it is unclear what force balances support the bipolarity of the spindle. This problem is especially difficult and important in cancer cells, which often have multiple centrosomes that somehow are able to cluster into two spindle poles. By using stochastic energy minimization in an effective energy landscape of the spindle and computationally screening forces, we find mechanical conditions for mono-, multi-and bi-polar spindles. We predict how microtubule and motor parameters have to be regulated in mitosis in multi-centrosomal cells.

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“…Thus, the regulation of kinesin-5-mediated force output does not occur through the modulation of the mechanochemical cycle of the motor, but instead by the regulation of the total force applied by an ensemble of motor molecules in response to geometrical features of cross-linked microtubules. This mode of regulation can be advantageous in a structure like the mitotic spindle, where kinesin-5 motors cross-link both the parallel bundles found near the spindle poles and anti-parallel bundles at the cell equator ( Shimamoto et al, 2015 ; Leary et al, 2019 ).…”

Section: Length and Polarity-dependent Regulation Of Map Activitymentioning

confidence: 99%

Micron-scale geometrical features of microtubules as regulators of microtubule organization

Mani

Wijeratne

Subramanian

2021

eLife

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The organization of micron-sized, multi-microtubule arrays from individual microtubules is essential for diverse cellular functions. The microtubule polymer is largely viewed as a passive building block during the organization process. An exception is the ‘tubulin code’ where alterations to tubulin at the amino acid level can influence the activity of microtubule-associated proteins. Recent studies reveal that micron-scale geometrical features of individual microtubules and polymer networks, such as microtubule length, overlap length, contact angle, and lattice defects, can also regulate the activity of microtubule-associated proteins and modulate polymer dynamics. We discuss how the interplay between such geometrical properties of the microtubule lattice and the activity of associated proteins direct multiple aspects of array organization, from microtubule nucleation and coalignment to specification of array dimensions and remodeling of dynamic networks. The mechanisms reviewed here highlight micron-sized features of microtubules as critical parameters to be routinely investigated in the study of microtubule self-organization.

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Successive Kinesin-5 Microtubule Crosslinking and Sliding Promote Fast, Irreversible Formation of a Stereotyped Bipolar Spindle

Cited by 17 publications

References 70 publications

The EB1–Kinesin-14 complex is required for efficient metaphase spindle assembly and kinetochore bi-orientation

The EB1–Kinesin-14 complex is required for efficient metaphase spindle assembly and kinetochore bi-orientation

Mechanics of Multicentrosomal Clustering in Bipolar Mitotic Spindles

Micron-scale geometrical features of microtubules as regulators of microtubule organization

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