Bipartite binding of the N terminus of Skp2 to cyclin A

Susan Kelso; Stephen Orlicky; Jonah Beenstock; Derek F Ceccarelli; Igor Kurinov; Gerald Gish; Frank Sicheri

doi:10.1016/j.str.2021.04.011

Bipartite binding of the N terminus of Skp2 to cyclin A

Structure. 2021 Sep 2;29(9):975-988.e5. doi: 10.1016/j.str.2021.04.011. Epub 2021 May 13.

Authors

Susan Kelso¹, Stephen Orlicky², Jonah Beenstock², Derek F Ceccarelli², Igor Kurinov³, Gerald Gish², Frank Sicheri⁴

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada.
² Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada.
³ Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Argonne, IL 60439, USA.
⁴ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, ON M5S 1A8, Canada. Electronic address: sicheri@lunenfeld.ca.

Abstract

Skp2 and cyclin A are cell-cycle regulators that control the activity of CDK2. Cyclin A acts as an activator and substrate recruitment factor of CDK2, while Skp2 mediates the ubiquitination and subsequent destruction of the CDK inhibitor protein p27. The N terminus of Skp2 can interact directly with cyclin A but is not required for p27 ubiquitination. To gain insight into this poorly understood interaction, we have solved the 3.2 Å X-ray crystal structure of the N terminus of Skp2 bound to cyclin A. The structure reveals a bipartite mode of interaction with two motifs in Skp2 recognizing two discrete surfaces on cyclin A. The uncovered binding mechanism allows for a rationalization of the inhibitory effect of Skp2 on CDK2-cyclin A kinase activity toward the RxL motif containing substrates and raises the possibility that other intermolecular regulators and substrates may use similar non-canonical modes of interaction for cyclin targeting.

Keywords: CDK; E3 ligase; E3 ubiquitin ligase; SCF; Skp2; cell cycle; crystal structure; cyclin; kinase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Binding Sites
Cyclin A / chemistry
Cyclin A / metabolism*
Humans
Molecular Docking Simulation
Protein Binding
S-Phase Kinase-Associated Proteins / chemistry*
S-Phase Kinase-Associated Proteins / metabolism

Substances

Cyclin A
S-Phase Kinase-Associated Proteins
SKP2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding