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Prime movers: the mechanochemistry of mitotic kinesins

Key Points

  • Crosslinking kinesins support the self-assembly and sliding of parallel or antiparallel microtubules in bundles to develop the bipolar symmetry of the spindle. These kinesins work in large teams, moving slowly and detaching slowly, which enables them to exert braking force as well as driving force and thereby control microtubule sliding rates.

  • Kinesin-13 family members (KIF2A, KIF2B and KIF2C in humans) are targeted to microtubule ends, which provokes depolymerization by stabilizing a curved conformation of tubulin in the cap. In the central spindle and elsewhere, this activity is balanced against microtubule polymerization and the sliding of microtubules in bundles.

  • One kinesin-14 family member, karyogamy 3 (Kar3; Saccharomyces cerevisiae), converts from a motor into a capping protein by heterodimerizing with chromosome instability and karyogamy 1 (Cik1) or vegetative interaction with Kar3 1 (Vik1), both of which have kinesin-like folds but no ATPase activity. This theme of mechanical control of the motor head by a non-motor partner might turn out to be a more general mechanism.

  • Several mitotic kinesins are processive (walking) dimers similar to kinesin-1. These are involved in the long-range transport of chromosomes.

  • Kinesin-8 (also known as KIF18 in humans) motors are multi-talented, with various isoforms reported to have depolymerase, polymerase, transporter and microtubule sliding functions. This should caution us that the properties of kinesins need to be measured and not inferred from homology searches.

  • Kinesin-5 (also known as KIF11 in humans) in yeast reverses direction in vitro depending on occupancy. It will be important to understand the molecular mechanism of this, to discover how many other kinesins do it and to understand the consequences for spindle self-organization.

Abstract

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation.

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Figure 1: Motorization of mitosis in human cells.
Figure 2: Topology of mitotic kinesins.
Figure 3: Force generation by mitotic kinesins: ATP gating and strain gating.
Figure 4: Elements of kinesin-driven spindle self-organization.

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Acknowledgements

The authors thank H. Drechsler and M. Mishima for their comments on the manuscript. The authors apologize to those whose work could not be discussed owing to space limitations.

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PowerPoint slides

Glossary

Self-organize

In a cell biology context, self-organization differs from molecular self-assembly in that it requires an energy source. Self-organization reactions are typically dynamic and reversible, whereas self-assembly reactions are spontaneous and generate a stable product.

Plus ends of microtubules

The fast-growing, relatively unstable ends of microtubules.

Minus ends of microtubules

The slow-growing, more stable ends of microtubules, as compared with the plus ends of microtubules.

Monastrol

A drug that binds to kinesin-5 family motors and locks them in a weak-binding (low friction) state.

Microtubule catastrophe

Where microtubules undergo dynamic instability, episodes of steady growth culminate in a sudden transition to rapid shrinkage called a catastrophe.

Stall force

Hindering force that prevents a motor from achieving net progress.

Unloaded velocity

The velocity with which the motor moves without a load.

ATP gate

A mechanism in which microtubule binding by one head of a two-headed (processive) kinesin depends on ATP binding to the other head.

Strain gate

A mechanism by which the unbinding of kinesin heads from microtubules is inhibited by backwards strain and promoted by forwards strain.

Prophase

The earliest stage of mitosis, in which the centrosomes separate and migrate.

Optical trapping experiments

Experiments in which a laser is used to trap a micron-sized transparent bead with a single kinesin molecule attached and then steered to bring the kinesin–bead complex into contact with a microtubule. The walking action of the kinesin can then be tracked by tracking the bead.

Cell cortex

Region of the cell that lies immediately beneath the plasma membrane; it is often actin rich.

Asters

Radial arrays of microtubules that are nucleated around a centrosome.

Kinetochores

Multi-protein complexes that assemble on the centromere of each chromosome. They form an attachment site for the plus ends of spindle microtubules.

Poleward microtubule flux

The translocation (flux) of tubulin towards the spindle pole that requires microtubule minus end depolymerization. Concurrent polymerization at plus ends will result in 'treadmilling'.

Paclitaxel

A drug that binds to microtubules and stabilizes them.

Congression

The migration of chromosomes to the spindle equator to form the metaphase plate.

Metaphase

The phase of mitosis when all chromosomes are positioned on the spindle equator.

Dynamicity

The frequency of switching between growth and shrinkage, and back again, at microtubule tips.

GTP–tubulin cap

The region at the growing end of a microtubule that is built from tubulins that are in a GTP-bound state.

Protofilaments

Microtubule protofilaments are built from tubulin heterodimers that are assembled head-to-tail. Protofilaments assemble side by side to form a sheet, and the sheet then rolls up into a tube.

Dolastatin

A drug that binds tubulin and inhibits microtubule assembly.

Chromokinesins

Kinesins that bind chromosomes.

Anaphase

The last stage of mitosis when sister chromatids are segregated to opposite ends of the mitotic spindle.

Central spindle

During anaphase, the mitotic spindle re-organizes in preparation for cytokinesis. Kinesin motor proteins and microtubule-associated proteins bundle the plus ends of interpolar microtubules into antiparallel microtubules and generate the central spindle, which regulates cleavage furrow initiation and the completion of cytokinesis.

Cytokinesis

A physical process after mitosis, in which the cell is divided into two new daughter cells.

Pre-anaphase

All stages of mitosis before anaphase, when the chromosomes begin to segregate to opposite poles of the spindle.

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Cross, R., McAinsh, A. Prime movers: the mechanochemistry of mitotic kinesins. Nat Rev Mol Cell Biol 15, 257–271 (2014). https://doi.org/10.1038/nrm3768

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