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Molecular architecture of the kinetochore–microtubule interface

Nature Reviews Molecular Cell Biology volume 9, pages 33–46 (2008)Cite this article

Key Points

  • The kinetochore is a large proteinaceous structure that mediates interactions between chromosomal DNA and spindle-microtubule polymers.

  • More than 80 kinetochore proteins have been identified using various genetic, functional, cell biology and proteomics approaches.

  • Specialized nucleosomes that contain the histone H3 variant CENP-A form the structural foundation for the kinetochore. A combination of sequence-independent epigenetic mechanisms ensure that CENP-A nucleosomes are directed to centromeres.

  • A combination of proteins form the interface with microtubules and provide distinct functions, including generating a core attachment site, coupling kinetochore movement to disassembling microtubules, affecting the polymerization dynamics of kinetochore-bound microtubules and driving translocation along spindle microtubules.

  • Multiple signalling pathways regulate the fidelity and timing of chromosome segregation and kinetochore function, including the mitotic checkpoint and several mitotic kinases.

Abstract

Segregation of the replicated genome during cell division in eukaryotes requires the kinetochore to link centromeric DNA to spindle microtubules. The kinetochore is composed of a number of conserved protein complexes that direct its specification and assembly, bind to spindle microtubules and regulate chromosome segregation. Recent studies have identified more than 80 kinetochore components, and are revealing how these proteins are organized into the higher order kinetochore structure, as well as how they function to achieve proper chromosome segregation.

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Figure 1: Mitotic chromosome segregation.
Figure 2: Vertebrate kinetochore ultrastructure.
Figure 3: Kinetochore specification.
Figure 4: Kinetochore composition is dynamically regulated during the cell cycle.
Figure 5: Molecular mechanisms underlying specific microtubule-directed activities at the kinetochore.

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Acknowledgements

We apologize to the many people whose work we were unable to cite owing to space constraints. We are grateful to Y. Dong and B. McEwen for providing the electron micrograph of the human kinetochore, and to R. Gassmann, D. Foltz, B. Weaver, P. Maddox, L. Jensen and T. Fukagawa for critical reading of the manuscript.

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Authors and Affiliations

  1. and Department of Biology, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Iain M. Cheeseman

  2. and Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, UCSD CMM-East, Room 3071G, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Arshad Desai

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Supplementary information

41580_2008_BFnrm2310_MOESM199_ESM.pdf

Supplementary information S1 (table) | Human kinetochore proteins identified to date with their likely homologues in budding yeast, fission yeast, nematodes, fruit fly and plants. (PDF 221 kb)

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Glossary

Transmission electron microscopy

A method that is used to image at high resolution by passing electrons through a sample that has been thinly sectioned and stained with heavy-metal compounds to generate contrast.

High-pressure freezing methods

Methods that are used to prepare samples for electron microscopy in which the sample is quickly cooled to low temperatures under high pressure. Preserves ultrastructure better than chemical fixation techniques.

Electron tomography

A technique in which sections that are larger than those typically used for transmission electron microscopy are imaged at various angles. Provides increased resolution and some three-dimensional imaging capacity.

α-satellite DNA

Repetitive DNA that is found at the centromeres of human cells.

HT1080 cells

Human cells that are used for the generation of artificial human chromosomes.

Dicentric chromosomes

Chromosomes that have two centromeres.

Neocentromeres

Chromosomal sites that do not contain typical repetitive centromeric DNA, but that do acquire centromeric chromatin, can assemble kinetochores, can recruit other centromeric proteins and are transmitted faithfully during meiosis and mitosis.

Acentric

A chromosome or chromosomal fragment that lacks a centromere.

SANT domain

A motif that was identified on the basis of its homology to the DNA-binding domain of c-Myb.

Coiled-coil domain

A protein structural domain that mediates subunit oligomerization or protein–protein interactions. Coiled coils contain between two and five α-helices that twist around each other to form a supercoil.

Minus end

The slower polymerizing end of a microtubule, in which α-tubulin is exposed. In cells, minus ends do not grow — they are either stable or depolymerizing.

Photobleaching assays

Experiments in which a fluorescently labelled protein that is localized to a specific site is exposed to a brief intense pulse of light to bleach the fluorescence, followed by recovery, during which unbleached protein from elsewhere (typically the cytoplasm) replaces the bleached protein. The time required for, and the extent of, the recovery provide information on the local dynamics of the protein at that site.

Calponin-homology domain

An ∼110-residue domain that is found in many cytoskeletal and signal-transduction proteins.

Plus end

The faster polymerizing end of a microtubule, in which β-tubulin is exposed.

Motor proteins

Mechanochemical enzymes that couple ATP hydrolysis to movement along a polymer lattice. The two major microtubule-directed motor protein families are the kinesins and dyneins.

Seam

Microtubules are composed of a series of linear protofilaments, which laterally associate and close to form a hollow cylindrical polymer. The seam is formed at the point of closure and is characterized by a change in the lateral tubulin–tubulin interactions relative to elsewhere in the polymer.

Cargo

Proteins that are carried along the polymer lattice by motor proteins.

Mitotic checkpoint pathway

The signal transduction pathway that is responsible for detecting chromosomes that are improperly attached to the mitotic spindle and arresting the cell cycle during metaphase until these errors have been corrected.

Helicase

An enzyme that unwinds double-stranded nucleic acids in an energy-dependent manner.

Polo-box domain

The portion of the polo kinase that is responsible for binding to substrates.

GTPase-activating protein

A protein that inactivates small GTP-binding proteins, such as Ras-family members, by increasing their rate of GTP hydrolysis.

AT-hook domain

A nine-amino-acid protein domain that binds to the minor groove of A and T rich DNA.

Nucleoporins

Protein subunits of the nuclear pore complex.

Aneuploidy

The ploidy of a cell refers to the number of chromosome sets that it contains. Aneuploid karyotypes are chromosome complements that are not a simple multiple of the haploid set.

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Cheeseman, I., Desai, A. Molecular architecture of the kinetochore–microtubule interface. Nat Rev Mol Cell Biol 9, 33–46 (2008). https://doi.org/10.1038/nrm2310

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