Cand1-Mediated Adaptive Exchange Mechanism Enables Variation in F-Box Protein Expression
Open accessAbstract
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 k off 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The conformational dynamics of unneddylated CRLs would enable transitioning between the different conformations coordinating cycles of neddylation/deneddylation with CAND1-driven substrate-receptor exchange.
“it seems likely that the conformational dynamics of unneddylated CRLs (Extended Data Figure 2) would enable transitioning between the different conformations coordinating cycles of neddylation/deneddylation with CAND1-driven substrate-receptor exchange39,46–49.”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [49]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity
Ran, F. A., Hsu, P. D., Lin, C.-Y., Gootenberg, J. S., Konermann, S., Trevino, A. E., Scott, D. A., Inoue, A., Matoba, S., Zhang, Y., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.021 · Cited by 3,299 · see citing works
Self-citationRING Domain E3 Ubiquitin Ligases
Deshaies, R. J., & Joazeiro, C. A. P. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.101807.093809 · Cited by 2,679 · see citing works
Self-citationAn inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
Soucy, T. A., Smith, P. G., Milhollen, M. A., Berger, A. J., Gavin, J. M., Adhikari, S., Brownell, J. E., Burke, K. E., Cardin, D. P., Critchley, S., et al. (2009) · Nature · doi:10.1038/nature07884 · Cited by 1,990 · see citing works
Kulak, N. A., Pichler, G., Paron, I., Nagaraj, N., & Mann, M. (2014) · Nature Methods · doi:10.1038/nmeth.2834 · Cited by 1,719 · see citing works
Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex
Zheng, N., Schulman, B. A., Song, L., Miller, J. J., Jeffrey, P. D., Wang, P., Chu, C., Koepp, D. M., Elledge, S. J., Pagano, M., et al. (2002) · Nature · doi:10.1038/416703a · Cited by 1,507 · see citing works
Raue, A., Kreutz, C., Maiwald, T., Bachmann, J., Schilling, M., Klingmüller, U., & Timmer, J. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp358 · Cited by 1,442 · see citing works
Beyond self-assembly: From microtubules to morphogenesis
Kirschner, M. W. (1986) · Cell · doi:10.1016/0092-8674(86)90318-1 · Cited by 1,362 · see citing works
Gene splicing and mutagenesis by PCR-driven overlap extension
Heckman, K. L., & Pease, L. R. (2007) · Nature Protocols · doi:10.1038/nprot.2007.132 · Cited by 1,150 · see citing works
Cellular motions and thermal fluctuations: the Brownian ratchet
Peskin, C. S., Odell, G. M., & OSTER, G. F. (1993) · Biophysical Journal · doi:10.1016/s0006-3495(93)81035-x · Cited by 896 · see citing works
Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects
Shen, B., Zhang, W., Zhang, J., Zhou, J., Wang, J.-Y., Chen, L., Wang, L., Hodgkins, A., Iyer, V., Huang, X., et al. (2014) · Nature Methods · doi:10.1038/nmeth.2857 · Cited by 827 · see citing works
Systematic analysis and nomenclature of mammalian F-box proteinsPreprint
Jin, J., Cardozo, T. J., Lovering, R. C., Elledge, S. J., Pagano, M., & Harper, J. W. (2004) · Genes & Development · doi:10.1101/gad.1255304 · Cited by 716 · see citing works
Protein neddylation: beyond cullin–RING ligases
Enchev, R. I., Schulman, B. A., & Peter, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3919 · Cited by 622 · see citing works
Insights into SCF ubiquitin ligases from the structure of the Skp1–Skp2 complex
Schulman, B. A., Carrano, A. C., Jeffrey, P. D., Bowen, Z., Kinnucan, E., Finnin, M. S., Elledge, S. J., Harper, J. W., Pagano, M., & Pavletich, N. P. (2000) · Nature · doi:10.1038/35042620 · Cited by 610 · see citing works
Signal-induced ubiquitination of Ikappa Balpha by the F-box protein Slimb/beta -TrCPPreprint
Spencer, E., Jiang, J., & Chen, Z. J. (1999) · Genes & Development · doi:10.1101/gad.13.3.284 · Cited by 434 · see citing works
An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis
Salahudeen, A. A., Thompson, J. W., Ruiz, J. C., Ma, H.-W., Kinch, L. N., Li, Q., Grishin, N. V., & Bruick, R. K. (2009) · Science · doi:10.1126/science.1176326 · Cited by 432 · see citing works
Multimodal Activation of the Ubiquitin Ligase SCF by Nedd8 Conjugation
Saha, A., & Deshaies, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.08.021 · Cited by 396 · see citing works
Self-citationDynamics of Cullin-RING Ubiquitin Ligase Network Revealed by Systematic Quantitative Proteomics
Bennett, E. J., Rush, A. J., Gygi, S. P., & Harper, J. W. (2010) · Cell · doi:10.1016/j.cell.2010.11.017 · Cited by 386 · see citing works
Xu, G., Mā, H., Nei, M., & Kong, H. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812043106 · Cited by 343 · see citing works
Partition analysis and concept of net rate constants as tools in enzyme kinetics
Cleland, W. W. (1975) · Biochemistry · doi:10.1021/bi00685a029 · Cited by 335 · see citing works
Building and remodelling Cullin–RING E3 ubiquitin ligases
Lydeard, J. R., Schulman, B. A., & Harper, J. W. (2013) · The EMBO Reports · doi:10.1038/embor.2013.173 · Cited by 327 · see citing works
NEDD8 Modification of CUL1 Dissociates p120CAND1, an Inhibitor of CUL1-SKP1 Binding and SCF Ligases
Liu, J., Furukawa, M., Matsumoto, T., & Xiong, Y. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00783-9 · Cited by 319 · see citing works
Goldenberg, S. J., Cascio, T. C., Shumway, S. D., Garbutt, K. C., Liu, J., Xiong, Y., & Zheng, N. (2004) · Cell · doi:10.1016/j.cell.2004.10.019 · Cited by 280 · see citing works
Cand1 Promotes Assembly of New SCF Complexes through Dynamic Exchange of F Box Proteins
Pierce, N. W., Lee, J. E., Liu, X., Sweredoski, M. J., Graham, R. L. J., Larimore, E. A., Rome, M., Zheng, N., Clurman, B. E., Hess, S., et al. (2013) · Cell · doi:10.1016/j.cell.2013.02.024 · Cited by 262 · see citing works
Self-citationTwo Distinct Types of E3 Ligases Work in Unison to Regulate Substrate Ubiquitylation
Scott, D. C., Rhee, D. Y., Duda, D. M., Kelsall, I. R., Olszewski, J. L., Paulo, J. A., de Jong, A., Ovaa, H., Alpi, A. F., Harper, J. W., et al. (2016) · Cell · doi:10.1016/j.cell.2016.07.027 · Cited by 229 · see citing works
Detection of sequential polyubiquitylation on a millisecond timescale
Pierce, N. W., Kleiger, G., Shan, S., & Deshaies, R. J. (2009) · Nature · doi:10.1038/nature08595 · Cited by 225 · see citing works
Self-citationThe Kinetic Mechanism of Ran-Nucleotide Exchange Catalyzed by RCC1
Klebe, C., Prinz, H., Wittinghofer, A., & Goody, R. S. (1995) · Biochemistry · doi:10.1021/bi00039a008 · Cited by 222 · see citing works
Substrate degradation by the proteasome: A single-molecule kinetic analysis
Lu, Y., Lee, B., King, R. W., Finley, D. J., & Kirschner, M. W. (2015) · Science · doi:10.1126/science.1250834 · Cited by 218 · see citing works
Structural regulation of cullin-RING ubiquitin ligase complexes
Duda, D. M., Scott, D. C., Calabrese, M. F., Zimmerman, E. S., Zheng, N., & Schulman, B. A. (2011) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2011.01.003 · Cited by 205 · see citing works
Scott, D. C., Sviderskiy, V. O., Monda, J. K., Lydeard, J. R., Cho, S. E., Harper, J. W., & Schulman, B. A. (2014) · Cell · doi:10.1016/j.cell.2014.04.037 · Cited by 201 · see citing works
Dcn1 Functions as a Scaffold-Type E3 Ligase for Cullin Neddylation
Kurz, T., Chou, Y.-C., Willems, A. R., Meyer‐Schaller, N., Hecht, M.-L., Tyers, M., Peter, M., & Sicheri, F. (2008) · Molecular Cell · doi:10.1016/j.molcel.2007.12.012 · Cited by 200 · see citing works
Targeted inhibition of the COP9 signalosome for treatment of cancer
Schlierf, A., Altmann, E., Quancard, J., Jefferson, A. B., Assenberg, R., Renatus, M., Jones, M. D., Hassiepen, U., Schaefer, M., Kiffe, M., et al. (2016) · Nature Communications · doi:10.1038/ncomms13166 · Cited by 192 · see citing works
Structural Basis for a Reciprocal Regulation between SCF and CSN
Enchev, R. I., Scott, D. C., da Fonseca, P. C. A., Schreiber, A., Monda, J. K., Schulman, B. A., Peter, M., & Morris, E. P. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.08.019 · Cited by 159 · see citing works
Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11
Li, J., Yakushi, T., Parlati, F., MacKinnon, A. L., Perez, C., Ma, Y., Carter, K. P., Colayco, S., Magnuson, G., Brown, B. T., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2326 · Cited by 159 · see citing works
Self-citationComposition and Regulation of the Cellular Repertoire of SCF Ubiquitin Ligases
Reitsma, J. M., Liu, X., Reichermeier, K. M., Moradian, A., Sweredoski, M. J., Hess, S. Y., & Deshaies, R. J. (2017) · Cell · doi:10.1016/j.cell.2017.10.016 · Cited by 144 · see citing works
Self-citationFeng, S., Shen, Y., Sullivan, J. A., Rubio, V., Xiong, Y., Sun, T., & Deng, X. W. (2004) · The Plant Cell · doi:10.1105/tpc.021949 · Cited by 137 · see citing works
Inducible Degradation of IκBα by the Proteasome Requires Interaction with the F-box Protein h-βTrCP
Kroll, M., Margottin-Goguet, F., Kohl, A., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.7941 · Cited by 130 · see citing works
F-Box-Directed CRL Complex Assembly and Regulation by the CSN and CAND1
Schmidt, M. W., McQuary, P. R., Wee, S., Hofmann, K., & Wolf, D. A. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.07.024 · Cited by 122 · see citing works
Monda, J. K., Scott, D. C., Miller, D. J., Lydeard, J. R., King, D., Harper, J. W., Bennett, E. J., & Schulman, B. A. (2012) · Structure · doi:10.1016/j.str.2012.10.013 · Cited by 121 · see citing works
CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire
Wu, S., Zhu, W., Nhan, T., Toth, J. I., Petroski, M. D., & Wolf, D. A. (2013) · Nature Communications · doi:10.1038/ncomms2636 · Cited by 118 · see citing works
Emberley, E. D., Mosadeghi, R., & Deshaies, R. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.352484 · Cited by 116 · see citing works
Self-citationChuang, H.-W., Zhang, W., & Gray, W. M. (2004) · The Plant Cell · doi:10.1105/tpc.021923 · Cited by 110 · see citing works
AtCAND1, A HEAT-Repeat Protein That Participates in Auxin Signaling in Arabidopsis
Cheng, Y., Dai, X., & Zhao, Y. (2004) · PLANT PHYSIOLOGY · doi:10.1104/pp.104.044495 · Cited by 107 · see citing works
CSN- and CAND1-dependent remodelling of the budding yeast SCF complex
Zemla, A., Thomas, Y., Kędziora, S., Knebel, A., Wood, N. T., Rabut, G. E. E., & Kurz, T. (2013) · Nature Communications · doi:10.1038/ncomms2628 · Cited by 101 · see citing works
CAND1-Mediated Substrate Adaptor Recycling Is Required for Efficient Repression of Nrf2 by Keap1
Lo, S., & Hannink, M. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.4.1235-1244.2006 · Cited by 99 · see citing works
Kamran, M., Long, Z.-J., Xu, D., et al. (2017) · Oncogenesis · doi:10.1038/oncsis.2016.80 · Cited by 98 · see citing works
SCCRO (DCUN1D1) Is an Essential Component of the E3 Complex for Neddylation
Kim, A. Y., Bommeljé, C. C., Lee, B. E., Yonekawa, Y., Choi, L., Morris, L. G. T., Huang, G., Kaufman, A., Ryan, R. J. H., Hao, B., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804440200 · Cited by 95 · see citing works
Mosadeghi, R., Reichermeier, K. M., Winkler, M., Schreiber, A., Reitsma, J. M., Zhang, Y., Stengel, F., Cao, J., Kim, M., Sweredoski, M. J., et al. (2016) · eLife · doi:10.7554/elife.12102 · Cited by 95 · see citing works
Self-citationSrinivasan, J., Dillman, A. R., Macchietto, M. G., Heikkinen, L., Lakso, M., Fracchia, K. M., Antoshechkin, I. A., Mortazavi, A., Wong, G., & Sternberg, P. W. (2013) · Genetics · doi:10.1534/genetics.112.148809 · Cited by 71 · see citing works
Goody, R. S., & Hofmann-Goody, W. (2002) · European Biophysics Journal · doi:10.1007/s00249-002-0225-3 · Cited by 67 · see citing works
Katayama, K., Noguchi, K., & Sugimoto, Y. (2013) · Cancer Science · doi:10.1111/cas.12145 · Cited by 64 · see citing works
Guanine Nucleotide Exchange Factors Operate by a Simple Allosteric Competitive Mechanism
Guo, Z., Ahmadian, M. R., & Goody, R. S. (2005) · Biochemistry · doi:10.1021/bi0518601 · Cited by 59 · see citing works
Characterization of the mammalian family of DCN-type NEDD8 E3 ligases
Keuss, M. J., Thomas, Y., McArthur, R., Wood, N. T., Knebel, A., & Kurz, T. (2016) · Journal of Cell Science · doi:10.1242/jcs.181784 · Cited by 54 · see citing works
Bosu, D. R., Feng, H., Min, K., Kim, Y., Wallenfang, M. R., & Kipreos, E. T. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.07.020 · Cited by 36 · see citing works
Chen, W., Xiong, S., Li, J., Li, X., Liu, Y., Zou, C., & Mallampalli, R. K. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.01185-14 · Cited by 30 · see citing works
Honarpour, N., Rose, C. M., Brumbaugh, J., Anderson, J., Graham, R. L. J., Sweredoski, M. J., Hess, S. Y., Coon, J. J., & Deshaies, R. J. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.031765 · Cited by 25 · see citing works
Self-citationA longevity protein, Lag2, interacts with SCF complex and regulates SCF function
Liu, Y., Mimura, S., Kishi, T., & Kamura, T. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.268 · Cited by 16 · see citing works
FBXO25 promotes cell proliferation, invasion, and migration of NSCLC
Jiang, G., Zhang, X., Wang, L., et al. (2016) · Tumor Biology · doi:10.1007/s13277-016-5298-1 · Cited by 15 · see citing works
Trade-off and flexibility in the dynamic regulation of the cullin-RING ubiquitin ligase repertoire
Straube, R., Shah, M., Flockerzi, D., & Wolf, D. A. (2017) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1005869 · Cited by 14 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly
Baek, K., Krist, D. T., Prabu, J. R., Hill, S., Klügel, M., Neumaier, L.-M., von Gronau, S., Kleiger, G., & Schulman, B. A. (2020) · Nature · doi:10.1038/s41586-020-2000-y · Cited by 270 · see citing works
Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly
Horn-Ghetko, D., Krist, D. T., Prabu, J. R., Baek, K., Mulder, M. P. C., Klügel, M., Scott, D. C., Ovaa, H., Kleiger, G., & Schulman, B. A. (2021) · Nature · doi:10.1038/s41586-021-03197-9 · Cited by 187 · see citing works
Mayor-Ruiz, C., Jaeger, M. G., Bauer, S., Brand, M., Sin, C., Hanzl, A., Mueller, A. C., Menche, J., & Winter, G. E. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.07.013 · Cited by 119 · see citing works
PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network
Reichermeier, K. M., Straube, R., Reitsma, J. M., Sweredoski, M. J., Rose, C. M., Moradian, A., den Besten, W., Hinkle, T., Verschueren, E., Petzold, G., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2019.12.013 · Cited by 78 · see citing works
Self-citation
- Authors
- Liu, X., Reitsma, J. M., Mamrosh, J. L., Zhang, Y., Straube, R., & Deshaies, R. J.
- Affiliations
- California Institute of Technology (US)
- Max Planck Institute for Dynamics of Complex Technical Systems (DE)
- Corresponding author
- Straube, Ronny
- Deshaies, Raymond J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 69
- Issue
- 5
- Pages
- 773-786.e6
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5836512
- OpenAlex
- W2791421524
- Cited by
- 108
- References
- 58
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 15 · 2023: 18 · 2022: 16 · 2021: 10 · 2020: 23 · 2019: 7 · 2018: 4
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- The Jane Coffin Childs Memorial Fund for Medical Research (JCCMF)
- JCCMF (GM112308)
- NIH (GM065997)
- Life Sciences Research Foundation
- Howard Hughes Medical Institute (HHMI)
- HHMI
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- SCF ubiquitin ligase, F-box protein, CAND1, neddylation, CUL1, substrate binding
- MeSH terms
- NEDD8 Protein, Animals, Gene Expression Regulation, Models, Biological, Models, Chemical, Transcription Factors, F-Box Proteins, Cullin Proteins, Mice, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
