Insights into SCF ubiquitin ligases from the structure of the Skp1–Skp2 complex

Brenda A. Schulman, Andrea C. Carrano, Philip D. Jeffrey, Zachary Bowen, Elspeth R. E. Kinnucan, Michael S. Finnin, Stephen J. Elledge, J. Wade Harper, Michele Pagano and Nikola P. Pavletich ()
Additional contact information
Brenda A. Schulman: Cellular Biochemistry and Biophysics Program
Andrea C. Carrano: NYU Medical Center
Philip D. Jeffrey: Cellular Biochemistry and Biophysics Program
Zachary Bowen: Cellular Biochemistry and Biophysics Program
Elspeth R. E. Kinnucan: Cellular Biochemistry and Biophysics Program
Michael S. Finnin: Cellular Biochemistry and Biophysics Program
Stephen J. Elledge: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
J. Wade Harper: Verna and Marrs McLean Department of Biochemistry
Michele Pagano: NYU Medical Center
Nikola P. Pavletich: Cellular Biochemistry and Biophysics Program

Nature, 2000, vol. 408, issue 6810, 381-386

Abstract: Abstract F-box proteins are members of a large family that regulates the cell cycle, the immune response, signalling cascades and developmental programmes by targeting proteins, such as cyclins, cyclin-dependent kinase inhibitors, IκBα and β-catenin, for ubiquitination (reviewed in refs 1,2,3). F-box proteins are the substrate-recognition components of SCF (Skp1–Cullin–F-box protein) ubiquitin-protein ligases4,5. They bind the SCF constant catalytic core by means of the F-box motif interacting with Skp1, and they bind substrates through their variable protein–protein interaction domains6. The large number of F-box proteins is thought to allow ubiquitination of numerous, diverse substrates6. Most organisms have several Skp1 family members, but the function of these Skp1 homologues and the rules of recognition between different F-box and Skp1 proteins remain unknown. Here we describe the crystal structure of the human F-box protein Skp2 bound to Skp1. Skp1 recruits the F-box protein through a bipartite interface involving both the F-box and the substrate-recognition domain. The structure raises the possibility that different Skp1 family members evolved to function with different subsets of F-box proteins, and suggests that the F-box protein may not only recruit substrate, but may also position it optimally for the ubiquitination reaction.

Date: 2000
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DOI: 10.1038/35042620

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