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An allosteric conduit facilitates dynamic multisite substrate recognition by the SCFCdc4 ubiquitin ligase

Author

Listed:
  • Veronika Csizmok

    (Molecular Structure & Function, The Hospital for Sick Children)

  • Stephen Orlicky

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital)

  • Jing Cheng

    (Institute for Research in Immunology and Cancer, Université de Montréal)

  • Jianhui Song

    (University of Toronto
    University of Toronto
    School of Polymer Science and Engineering, Qingdao University of Science and Technology)

  • Alaji Bah

    (Molecular Structure & Function, The Hospital for Sick Children)

  • Neda Delgoshaie

    (Institute for Research in Immunology and Cancer, Université de Montréal)

  • Hong Lin

    (Molecular Structure & Function, The Hospital for Sick Children)

  • Tanja Mittag

    (Molecular Structure & Function, The Hospital for Sick Children
    Present address: Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA)

  • Frank Sicheri

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto
    University of Toronto)

  • Hue Sun Chan

    (University of Toronto
    University of Toronto)

  • Mike Tyers

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    Institute for Research in Immunology and Cancer, Université de Montréal
    Present address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel 4058, Switzerland)

  • Julie D. Forman-Kay

    (Molecular Structure & Function, The Hospital for Sick Children
    University of Toronto)

Abstract

The ubiquitin ligase SCFCdc4 mediates phosphorylation-dependent elimination of numerous substrates by binding one or more Cdc4 phosphodegrons (CPDs). Methyl-based NMR analysis of the Cdc4 WD40 domain demonstrates that Cyclin E, Sic1 and Ash1 degrons have variable effects on the primary Cdc4WD40 binding pocket. Unexpectedly, a Sic1-derived multi-CPD substrate (pSic1) perturbs methyls around a previously documented allosteric binding site for the chemical inhibitor SCF-I2. NMR cross-saturation experiments confirm direct contact between pSic1 and the allosteric pocket. Phosphopeptide affinity measurements reveal negative allosteric communication between the primary CPD and allosteric pockets. Mathematical modelling indicates that the allosteric pocket may enhance ultrasensitivity by tethering pSic1 to Cdc4. These results suggest negative allosteric interaction between two distinct binding pockets on the Cdc4WD40 domain may facilitate dynamic exchange of multiple CPD sites to confer ultrasensitive dependence on substrate phosphorylation.

Suggested Citation

  • Veronika Csizmok & Stephen Orlicky & Jing Cheng & Jianhui Song & Alaji Bah & Neda Delgoshaie & Hong Lin & Tanja Mittag & Frank Sicheri & Hue Sun Chan & Mike Tyers & Julie D. Forman-Kay, 2017. "An allosteric conduit facilitates dynamic multisite substrate recognition by the SCFCdc4 ubiquitin ligase," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms13943
    DOI: 10.1038/ncomms13943
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