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EMBO Rep. 2018 May;19(5). pii: e44742. doi: 10.15252/embr.201744742. Epub 2018 Apr 9.

Disentangling the molecular determinants for Cenp-F localization to nuclear pores and kinetochores.

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Institut Jacques Monod, UMR7592, CNRS, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Ecole Doctorale Structure et Dynamique des Systèmes Vivants (#577), Univ Paris Sud, Université Paris-Saclay, Orsay, France.
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris Sud, Université Paris-Saclay, Gif sur Yvette, France.
Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
Institut Jacques Monod, UMR7592, CNRS, Université Paris Diderot, Sorbonne Paris Cité, Paris, France


Cenp-F is a multifaceted protein implicated in cancer and developmental pathologies. The Cenp-F C-terminal region contains overlapping binding sites for numerous proteins that contribute to its functions throughout the cell cycle. Here, we focus on the nuclear pore protein Nup133 that interacts with Cenp-F both at nuclear pores in prophase and at kinetochores in mitosis, and on the kinase Bub1, known to contribute to Cenp-F targeting to kinetochores. By combining in silico structural modeling and yeast two-hybrid assays, we generate an interaction model between a conserved helix within the Nup133 β-propeller and a short leucine zipper-containing dimeric segment of Cenp-F. We thereby create mutants affecting the Nup133/Cenp-F interface and show that they prevent Cenp-F localization to the nuclear envelope, but not to kinetochores. Conversely, a point mutation within an adjacent leucine zipper affecting the kinetochore targeting of Cenp-F KT-core domain impairs its interaction with Bub1, but not with Nup133, identifying Bub1 as the direct KT-core binding partner of Cenp-F. Finally, we show that Cenp-E redundantly contributes together with Bub1 to the recruitment of Cenp-F to kinetochores.


Cenp‐F; in silico modeling; kinetochores; mitosin; nuclear pore

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