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Traffic control: regulation of kinesin motors

Key Points

  • Kinesins are a superfamily of molecular motors that generate force and/or motility along microtubule filaments. Kinesins contain a conserved motor domain for ATP hydrolysis and microtubule binding, and divergent non-motor domains for family-specific regulatory mechanisms and functions.

  • The regulation of kinesin motors ensures their proper spatial and temporal activation. A general model is emerging in which kinesin motors are kept inactive by autoinhibitory mechanisms. Recent work has shown that this autoinhibition can be relieved by cargo binding and/or phosphorylation mechanisms.

  • Some kinesin motors drive intracellular transport events during interphase. The association of motors with specific cargos for transport can be regulated by kinases and Rab GTPases. Kinesin-driven cargo transport can be influenced by the state of the microtubule tracks, specifically by post-translational modifications or microtubule-associated proteins on the tracks. The release of cargo at the destination can be regulated by kinases that are part of signalling pathways, which can also be cargos of the motor.

  • Kinesin motors also function in spindle assembly and chromosome segregation during mitosis. The expression levels of these kinesin motors can be regulated by controlling their synthesis anddegradation at different stages of the cell cycle.

  • Mitotic kinesin motors can also be regulated by the small GTPase Ran and by cyclin-dependent kinase, Aurora and Polo-like kinases. These regulatory mechanisms ensure the proper localization and activation of kinesin motors at specific stages of the mitotic cycle.

Abstract

Kinesins are a family of molecular motors that use the energy of ATP hydrolysis to move along the surface of, or destabilize, microtubule filaments. Much progress has been made in understanding the mechanics and functions of the kinesin motors that play important parts in cell division, cell motility, intracellular trafficking and ciliary function. How kinesins are regulated in cells to ensure the temporal and spatial fidelity of their microtubule-based activities is less well understood. Recent work has revealed molecular mechanisms that control kinesin autoinhibition and subsequent activation, binding to cargos and microtubule tracks, and localization at specific sites of action.

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Figure 1: Autoinhibitory mechanisms used by kinesin motors.
Figure 2: Transport cycle of kinesin motors.
Figure 3: Kinesin motor localization during mitosis in mammalian cells.
Figure 4: Mechanisms of mitotic motor regulation.

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Acknowledgements

We are grateful to D. Cai, J. Howard, C. Walczak and S. Gilbert for helpful discussions.

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Glossary

Ciliopathies

A collection of human diseases that have a common underlying genetic defect in the assembly or function of cilia.

Coiled coil

A structural motif in proteins, often used to control oligomerization, in which two or more coils — α-helical seven amino acid (heptad) repeats — wrap around each other.

Kinesin heavy chain

The catalytic subunit of a Kinesin-1 motor, the domain organization of which consists of a kinesin motor domain, a coiled-coil stalk and a globular tail.

Kinesin light chain

The accessory subunit of a Kinesin-1 motor that contributes to autoinhibition and is important for binding to some cargos.

MAPK family

(Mitogen-activated protein kinase family). A family of Ser/Thr-specific protein kinases that respond to extracellular signals and regulate a range of intracellular events. The MAPK is the third kinase in a cascade and is activated by a MAPK kinase (MAPKK), which is activated by a MAPKK kinase (MAPKKK).

Intraflagellar transport

The system for bidirectional movement of ciliary components along the ciliary axoneme by Kinesin-2 and cytoplasmic dynein motors.

EF hand

A structural domain in proteins that binds to Ca2+ ions.

Guanine nucleotide exchange factor

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a G protein.

Karyogamy

The process during mating in which two haploid nuclei come together and fuse to form a diploid nucleus.

Centrosome

A microtubule organizing centre that contains centrioles and the pericentriolar material that nucleates microtubule polymerization. It duplicates during S phase to create the spindle poles for mitosis.

Metaphase plate

The plane at mid-spindle, perpendicular to the spindle microtubules, where the chromosomes are positioned during metaphase.

Kinetochore

A multiprotein complex that assembles on the centromeric region of chromosomes and attaches to spindle microtubules. The inner kinetochore contains proteins that are tightly and persistently associated with centromeric DNA, whereas the outer kinetochore contains dynamic protein components that interact with microtubules during mitosis.

Mitotic checkpoint

A control mechanism in metaphase that ensures that all chromosomes are properly attached to both spindle poles before the cell can proceed into anaphase.

Chromosome congression

The process by which chromosomes attach to spindle microtubules and align or 'congress' to the metaphase plate. It requires both microtubule dynamics and kinesin motor activities.

Prenylation

A post-translational modification of a protein by the attachment of prenyl moieties (geranyl, farnesyl or geranylgeranyl groups) to a C-terminal Cys residue.

Chromosomal passenger complex

A multiprotein complex that localizes to the kinetochore until early anaphase, when it switches to the central spindle. It consists of the Aurora B kinase, inner centromere protein, survivin and Borealin (also known as Dasra and CDCA8).

Merotelic

Pertains to an incorrect spindle attachment in which a single kinetochore is attached to microtubules from both spindle poles.

Amphitelic

Pertains to a proper spindle attachment in which each sister kinetochore is attached to the microtubules from its nearest facing spindle pole.

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Verhey, K., Hammond, J. Traffic control: regulation of kinesin motors. Nat Rev Mol Cell Biol 10, 765–777 (2009). https://doi.org/10.1038/nrm2782

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