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The Sak polo-box comprises a structural domain sufficient for mitotic subcellular localization

Nature Structural Biology volume 9, pages 719–724 (2002)Cite this article

Abstract

The small family of polo-like kinases (Plks) includes Cdc5 from Saccharomyces cerevisiae, Plo1 from Schizosaccharomyces pombe, Polo from Drosophila melanogaster and the four mammalian genes Plk1, Prk/Fnk, Snk and Sak. These kinases control cell cycle progression through the regulation of centrosome maturation and separation, mitotic entry, metaphase to anaphase transition, mitotic exit and cytokinesis. Plks are characterized by an N-terminal Ser/Thr protein kinase domain and the presence of one or two C-terminal regions of similarity, termed the polo box motifs. These motifs have been demonstrated for Cdc5 and Plk1 to be required for mitotic progression and for subcellular localization to mitotic structures. Here we report the 2.0 Å crystal structure of a novel domain composed of the polo box motif of murine Sak. The structure consists of a dimeric fold with a deep interfacial cleft and pocket, suggestive of a ligand-binding site. We show that this domain forms homodimers both in vitro and in vivo, and localizes to centrosomes and the cleavage furrow during cytokinesis. The requirement of the polo domain for Plk family function and the unique physical properties of the domain identify it as an attractive target for inhibitor design.

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Figure 1: Structure-based sequence alignment of the Plk family polo domains.
Figure 2: Structure of the Sak polo domain dimer.
Figure 3: The polo domain of Sak can self-associate in vivo but Sak may use several mechanisms for self-association.
Figure 4: Subcellular localization of EGFP-fusion proteins demonstrate that the polo domain of Sak is sufficient for localization.

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Acknowledgements

We thank I. Blasutig, S.H. Ong, S. Oster, L. Harrington, D. Durocher and P. Plant for helpful discussion and assistance with the coimmunoprecipitation experiments, and P. Taylor and B. Larsen for instruction on mass spectrometry. We also thank the BioCars and Structural Biology Centre staff at the Advanced Photon Source at Argonne National Laboratories, where diffraction data were collected. This work was supported by grants from the National Cancer Institute of Canada to F.S. and J.D. F.S. is a recipient of a National Cancer Institute of Canada Scientist award. G.C.L is a recipient of a Natural Sciences and Engineering Research Council of Canada award.

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  1. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Genie C. Leung, John W. Hudson, Anna Kozarova, James W. Dennis & Frank Sicheri

  2. Department of Molecular and Medical Genetics, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Genie C. Leung, Alan Davidson, James W. Dennis & Frank Sicheri

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Correspondence to Frank Sicheri.

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Leung, G., Hudson, J., Kozarova, A. et al. The Sak polo-box comprises a structural domain sufficient for mitotic subcellular localization. Nat Struct Mol Biol 9, 719–724 (2002). https://doi.org/10.1038/nsb848

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