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

Veronika Csizmok, Stephen Orlicky, Jing Cheng, Jianhui Song, Alaji Bah, Neda Delgoshaie, Hong Lin, Tanja Mittag, Frank Sicheri, Hue Sun Chan, Mike Tyers and Julie D. Forman-Kay ()
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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
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
Frank Sicheri: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Hue Sun Chan: University of Toronto
Mike Tyers: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Julie D. Forman-Kay: Molecular Structure & Function, The Hospital for Sick Children

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms13943

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