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

Liu, Xing and Reitsma, Justin M. and Mamrosh, Jennifer L. and Zhang, Yaru and Straube, Ronny and Deshaies, Raymond J. (2018) Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression. Molecular Cell, 69 (5). pp. 773-786. ISSN 1097-2765. PMCID PMC5836512. http://resolver.caltech.edu/CaltechAUTHORS:20180301-131842787

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.molcel.2018.01.038DOIArticle
https://www.sciencedirect.com/science/article/pii/S1097276518300972PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836512/PubMed CentralArticle
ORCID:
AuthorORCID
Deshaies, Raymond J.0000-0002-3671-9354
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.
Funders:
Funding AgencyGrant Number
Jane Coffin Childs Memorial Fund for Medical ResearchUNSPECIFIED
NIHGM112308
Life Sciences Research FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIHGM065997
Subject Keywords:Cand1; exchange factor; ubiquitin ligase; SCF cycle; mathematical modeling
PubMed Central ID:PMC5836512
Record Number:CaltechAUTHORS:20180301-131842787
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180301-131842787
Official Citation:Xing Liu, Justin M. Reitsma, Jennifer L. Mamrosh, Yaru Zhang, Ronny Straube, Raymond J. Deshaies, Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression, Molecular Cell, Volume 69, Issue 5, 1 March 2018, Pages 773-786.e6, ISSN 1097-2765, https://doi.org/10.1016/j.molcel.2018.01.038. (https://www.sciencedirect.com/science/article/pii/S1097276518300972)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85041
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:01 Mar 2018 21:31
Last Modified:09 Apr 2018 22:01

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