Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published March 1, 2018 | Supplemental Material
Journal Article Open

Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression


Skp1⋅Cul1⋅F-box (SCF) ubiquitin ligase assembly is regulated by the interplay of substrate binding, reversible Nedd8 conjugation on Cul1, and the F-box protein (FBP) exchange factors Cand1 and Cand2. Detailed investigations into SCF assembly and function in reconstituted systems and Cand1/2 knockout cells informed the development of a mathematical model for how dynamical assembly of SCF complexes is controlled and how this cycle is coupled to degradation of an SCF substrate. Simulations predicted an unanticipated hypersensitivity of Cand1/2-deficient cells to FBP expression levels, which was experimentally validated. Together, these and prior observations lead us to propose the adaptive exchange hypothesis, which posits that regulation of the koff of an FBP from SCF by the actions of substrate, Nedd8, and Cand1 molds the cellular repertoire of SCF complexes and that the plasticity afforded by this exchange mechanism may enable large variations in FBP expression during development and in FBP gene number during evolution.

Additional Information

© 2018 Elsevier Inc. Received 5 October 2017, Revised 8 January 2018, Accepted 29 January 2018, Available online 1 March 2018. Author Contributions: Conceptualization, X.L., R.S., and R.J.D.; Methodology and Investigation, X.L., J.M.R., Y.Z., and J.L.M.; Methodology and Software, R.S.; Writing, X.L., R.S., and R.J.D.; Supervision, X.L., R.S., and R.J.D.; Funding Acquisition, X.L., J.M.R., and R.J.D. Declaration of Interests: R.J.D. is an employee and shareholder of Amgen. We thank Brenda Schulman, Ning Zheng, and William den Besten for gifts of reagents; Novartis for providing the CSN5i-3 compound; Shu-Ou Shan for sharing instruments; Lea Goentoro and Noah Olsman for insightful discussion on the mathematical model; Robert J. Flassig for discussions on parameter estimation; and all the members of the Deshaies lab for helpful discussions. X.L. is a fellow of The Jane Coffin Childs Memorial Fund for Medical Research (JCCMF), and this investigation has been aided by a grant from JCCMF. J.M.R. is supported by F32 grant GM112308 from NIH. J.L.M. is supported by Life Sciences Research Foundation. R.J.D. was an investigator of the Howard Hughes Medical Institute (HHMI), and this work was supported in part by HHMI and NIH GM065997 to R.J.D.

Attached Files

Supplemental Material - mmc1.pdf


Files (9.3 MB)
Name Size Download all
9.3 MB Preview Download

Additional details

August 21, 2023
October 18, 2023