Abstract
Polo-like kinase-1 (Plk1) has a pivotal role in cell proliferation and is considered a potential target for anticancer therapy. The noncatalytic polo-box domain (PBD) of Plk1 forms a phosphoepitope binding module for protein-protein interaction. Here, we report the identification of minimal phosphopeptides that specifically interact with the PBD of human PLK1, but not those of the closely related PLK2 and PLK3. Comparative binding studies and analyses of crystal structures of the PLK1 PBD in complex with the minimal phosphopeptides revealed that the C-terminal SpT dipeptide functions as a high-affinity anchor, whereas the N-terminal residues are crucial for providing specificity and affinity to the interaction. Inhibition of the PLK1 PBD by phosphothreonine mimetic peptides was sufficient to induce mitotic arrest and apoptotic cell death. The mode of interaction between the minimal peptide and PBD may provide a template for designing therapeutic agents that target PLK1.
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Change history
21 September 2010
In the version of this article initially published, two of the numbers shown in Table 1 had the wrong sign. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank F.J. Gonzalez, C. Vinson and S. Garfield for critical reading of the manuscript, and R. Erikson (Harvard University) and W. Dai (New York University School of Medicine) for reagents and helpful suggestions. This research was supported in part by the Intramural Research Program of the National Cancer Institute (E.A., J.B.M., M.C.N., T.R.B., A.W. and K.S.L.), National Institutes of Health grant R01 GM60594 (M.B.Y.), Korea Basic Science Institute project N28079 (J.K.B.), a Korean Ministry of Education grant (D.H.L.) and a Japanese government grant (A.O.). This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 and HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.
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K.S.L., T.M., D.L., J.-E.P., S.R.S., F.L., Y.H.K., A.W., M.B.Y. and T.R.B. designed the experiments; S.-M.Y., T.M., D.L., J.K.B., J.-E.P., S.R.S., F.L., Y.H.K., C.L., N.-K.S. and S.L. conducted the experiments; K.S.L., T.M., D.L., S.R.S., A.W., M.B.Y., T.R.B., J.B.M., D.-H.L., M.C.N., E.A., A.O., D.-Y.Y. and Y.L. analyzed the data; and K.S.L., T.M., D.L., S.R.S., A.W., M.B.Y., F.L. and T.R.B. wrote the paper.
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Yun, SM., Moulaei, T., Lim, D. et al. Structural and functional analyses of minimal phosphopeptides targeting the polo-box domain of polo-like kinase 1. Nat Struct Mol Biol 16, 876–882 (2009). https://doi.org/10.1038/nsmb.1628
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DOI: https://doi.org/10.1038/nsmb.1628
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