Structural Insights into NEDD8 Activation of Cullin-RING Ligases: Conformational Control of Conjugation
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Cullin-RING ligases (CRLs) comprise the largest ubiquitin E3 subclass, in which a central cullin subunit links a substrate-binding adaptor with an E2-binding RING. Covalent attachment of the ubiquitin-like protein NEDD8 to a conserved C-terminal domain (ctd) lysine stimulates CRL ubiquitination activity and prevents binding of the inhibitor CAND1. Here we report striking conformational rearrangements in the crystal structure of NEDD8~Cul5(ctd)-Rbx1 and SAXS analysis of NEDD8~Cul1(ctd)-Rbx1 relative to their unmodified counterparts. In NEDD8ylated CRL structures, the cullin WHB and Rbx1 RING subdomains are dramatically reoriented, eliminating a CAND1-binding site and imparting multiple potential catalytic geometries to an associated E2. Biochemical analyses indicate that the structural malleability is important for both CRL NEDD8ylation and subsequent ubiquitination activities. Thus, our results point to a conformational control of CRL activity, with ligation of NEDD8 shifting equilibria to disfavor inactive CAND1-bound closed architectures, and favor dynamic, open forms that promote polyubiquitination.
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UB transfer from a RING-docked UBE2D~UB intermediate to an F-box protein-bound substrate is difficult to rationalize by prior structural models or by the paper's cryo EM reconstructions of unneddylated and neddylated substrate-bound CRL1β-TRCP.
“UB transfer from a RING-docked UBE2D~UB intermediate (“~” indicates thioester bond/thioester-bond mimic) to an F-box protein-bound substrate is difficult to rationalize by prior structural models 3,7,20,27, or by our cryo EM reconstructions of unneddylated and neddylated substrate-bound CRL1β-TRCP”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [3]
A neddylated CUL5-RBX1 domain structure (PDB ID 3DQV) revealed potential for neddylated CUL WHB and RBX1 RING domain conformational changes.
“a structure of a neddylated CUL5-RBX1 domain (PDB ID 3DQV, labeled “Post-Neddylation”, which revealed potential for neddylated CUL WHB and RBX1 RING domain conformational changes3, and data herein shows is dynamic)”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [3]
The flexible tether of CUL1 Helix-29 rationalizes the previously observed proteolytic sensitivity of this region in a neddylated CUL1-RBX1 complex.
“which rationalizes the previously observed proteolytic sensitivity of this region in a neddylated CUL1-RBX1 complex3”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [3]
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[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475 · see citing works
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
Svergun, D. I. (1992) · Journal of Applied Crystallography · doi:10.1107/s0021889892001663 · Cited by 3,876 · see citing works
Automated MAD and MIR structure solution
Terwilliger, T. C., & Berendzen, J. (1999) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444999000839 · Cited by 3,038 · see citing works
Function and regulation of cullin–RING ubiquitin ligases
Petroski, M. D., & Deshaies, R. J. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1547 · Cited by 2,148 · see citing works
Röntgenuntersuchung gelöster Fadenmoleküle
Kratky, O., & Porod, G. (1949) · Recueil des Travaux Chimiques des Pays-Bas · doi:10.1002/recl.19490681203 · Cited by 1,988 · see citing works
Modification of Proteins by Ubiquitin and Ubiquitin-Like Proteins
Kerscher, O., Felberbaum, R. S., & Hochstrasser, M. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.22.010605.093503 · Cited by 1,521 · 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
Self-citationInduction of APOBEC3G Ubiquitination and Degradation by an HIV-1 Vif-Cul5-SCF Complex
Yu, X., Yu, Y., Liu, B., Luo, K., Kong, W., Mao, P., & Yu, X.-F. (2003) · Science · doi:10.1126/science.1089591 · Cited by 1,194 · see citing works
Likelihood-enhanced fast rotation functions
Storoni, L. C., McCoy, A. J., & Read, R. J. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444903028956 · Cited by 1,177 · see citing works
The SCF ubiquitin ligase: insights into a molecular machine
Cardozo, T., & Pagano, M. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1471 · Cited by 1,114 · see citing works
Polyubiquitin chains: polymeric protein signals
Pickart, C. M., & Fushman, D. (2004) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2004.09.009 · Cited by 1,052 · see citing works
Structure of a c-Cbl–UbcH7 Complex
Zheng, N., Wang, P., Jeffrey, P. D., & Pavletich, N. P. (2000) · Cell · doi:10.1016/s0092-8674(00)00057-x · Cited by 839 · see citing works
Li, W., Bengtson, M. H., Ulbrich, A., Matsuda, A., Reddy, V. A., Orth, A. P., Chanda, S. K., Batalov, S., & Joazeiro, C. A. P. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001487 · Cited by 839 · see citing works
Promotion of NEDD8-CUL1 Conjugate Cleavage by COP9 Signalosome
Lyapina, S., Cope, G. A., Shevchenko, A., Serino, G., Tsuge, T., Zhou, C., Wolf, D. A., Wei, N., Shevchenko, A., & Deshaies, R. J. (2001) · Science · doi:10.1126/science.1059780 · Cited by 699 · see citing works
Phosphorylation‐dependent degradation of the cyclin‐dependent kinase inhibitor p27Kip1
Vlach, J., Hennecke, S., & Amati, B. B. (1997) · The EMBO Journal · doi:10.1093/emboj/16.17.5334 · Cited by 687 · see citing works
Molecular architecture and assembly of the DDB1–CUL4A ubiquitin ligase machinery
Angers, S., Li, T., Yi, X., MacCoss, M. J., Moon, R. T., & Zheng, N. (2006) · Nature · doi:10.1038/nature05175 · Cited by 674 · see citing works
Structure of a β-TrCP1-Skp1-β-Catenin Complex
Wu, G., Xu, G., Schulman, B. A., Jeffrey, P. D., Harper, J. W., & Pavletich, N. P. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00234-x · Cited by 612 · see citing works
Self-citationInsights 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
Self-citationBrown, N. R., Noble, M. E. M., Endicott, J., & Johnson, L. N. (1999) · Nature Cell Biology · doi:10.1038/15674 · Cited by 546 · see citing works
Orlicky, S. M., Tang, X., Willems, A. R., Tyers, M., & Sicheri, F. (2003) · Cell · doi:10.1016/s0092-8674(03)00034-5 · Cited by 510 · see citing works
Querido, E., Blanchette, P., Yan, Q., Kamura, T., Morrison, M. R., Boivin, D., Kaelin, W. G., Conaway, R. C., Conaway, J. W., & Branton, P. E. (2001) · Genes & Development · doi:10.1101/gad.926401 · Cited by 480 · see citing works
Kamura, T., Maenaka, K., Kotoshiba, S., Matsumoto, M., Kohda, D., Conaway, R. C., Conaway, J. W., & Nakayama, K. I. (2004) · Genes & Development · doi:10.1101/gad.1252404 · Cited by 476 · see citing works
Nedd8 on cullin: building an expressway to protein destruction
Pan, Z., Kentsis, A., Dias, D. C., Yamoah, K., & Wu, K. K.-Y. (2004) · Oncogene · doi:10.1038/sj.onc.1207414 · Cited by 430 · see citing works
Nedd8 Modification of Cul-1 Activates SCF<sup>βTrCP</sup>-Dependent Ubiquitination of IκBα
Read, M. A., Brownell, J. E., Gladysheva, T. B., Hottelet, M., Parent, L. A., Coggins, M. B., Pierce, J. W., Podust, V. N., Luo, R.-S., Chau, V., et al. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.7.2326-2333.2000 · Cited by 363 · see citing works
NEDD8 recruits E2‐ubiquitin to SCF E3 ligase
Kawakami, T., Chiba, T., Suzuki, T., Iwai, K., Yamanaka, K., Minato, N., Suzuki, H., Shimbara, N., Hidaka, Y., Osaka, F., et al. (2001) · EMBO Journal · doi:10.1093/emboj/20.15.4003 · Cited by 344 · see citing works
Wu, G., Xu, G., Schulman, B. A., Jeffrey, P. D., Harper, J. W., & Pavletich, N. P. (2003) · Molecules and Cells · Cited by 333 · see citing works
Self-citationNEDD8 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
A UbcH5/Ubiquitin Noncovalent Complex Is Required for Processive BRCA1-Directed Ubiquitination
Brzović, P. S., Lissounov, A., Christensen, D. E., Hoyt, D. W., & Klevit, R. E. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.02.008 · Cited by 311 · see citing works
CAND1 Binds to Unneddylated CUL1 and Regulates the Formation of SCF Ubiquitin E3 Ligase Complex
Zheng, J., Yang, X., Harrell, J. M., Ryzhikov, S., Shim, E., Lykke‐Hartmann, K., Wei, N., Sun, H., Kobayashi, R., & Zhang, H. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00784-0 · Cited by 309 · see citing works
Structural Basis of the Cks1-Dependent Recognition of p27Kip1 by the SCFSkp2 Ubiquitin Ligase
Hao, B., Zheng, N., Schulman, B. A., Wu, G., Miller, J. J., Pagano, M., & Pavletich, N. P. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.09.003 · Cited by 306 · see citing works
Self-citationAutoinhibition of the HECT-Type Ubiquitin Ligase Smurf2 through Its C2 Domain
Wiesner, S., Ogunjimi, A. A., Wang, H., Rotin, D., Sicheri, F., Wrana, J. L., & Forman-Kay, J. D. (2007) · Cell · doi:10.1016/j.cell.2007.06.050 · Cited by 283 · see citing works
Conformational Flexibility Underlies Ubiquitin Ligation Mediated by the WWP1 HECT Domain E3 Ligase
Verdecia, M. A., Joazeiro, C. A. P., Wells, N. J., Ferrer, J.-L., Bowman, M. E., Hunter, T. R., & Noel, J. P. (2003) · Molecular Cell · doi:10.1016/s1097-2765(02)00774-8 · Cited by 282 · 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
Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change
Gallagher, E. D., Gao, M., Liu, Y., & Karin, M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510664103 · Cited by 277 · see citing works
Kamura, T., Conrad, M. N., Yan, Q., Conaway, R. C., & Conaway, J. W. (1999) · Genes & Development · doi:10.1101/gad.13.22.2928 · Cited by 270 · see citing works
Structural Mechanisms Underlying Posttranslational Modification by Ubiquitin-Like Proteins
Dye, B. T., & Schulman, B. A. (2007) · Annual Review of Biophysics and Biomolecular Structure · doi:10.1146/annurev.biophys.36.040306.132820 · Cited by 264 · see citing works
Self-citationA Nedd8 conjugation pathway is essential for proteolytic targeting of p27 Kip1 by ubiquitination
Podust, V. N., Brownell, J. E., Gladysheva, T. B., Luo, R.-S., Wang, C., Coggins, M. B., Pierce, J. W., Lightcap, E. S., & Chau, V. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090465597 · Cited by 244 · see citing works
Basis for a ubiquitin-like protein thioester switch toggling E1–E2 affinity
Huang, D. T. C., Hunt, H. W., Zhuang, M., Ohi, M. D., Holton, J. M., & Schulman, B. A. (2007) · Nature · doi:10.1038/nature05490 · Cited by 227 · see citing works
Self-citationAnalysis of the Adenovirus E1B-55K-Anchored Proteome Reveals Its Link to Ubiquitination Machinery
Harada, J. N., Shevchenko, A., Shevchenko, A., Pallas, D. C., & Berk, A. J. (2002) · Journal of Virology · doi:10.1128/jvi.76.18.9194-9206.2002 · Cited by 218 · see citing works
Wu, K. K.-Y., Chen, A., & Pan, Z. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004847200 · Cited by 204 · see citing works
Structural Basis for Recruitment of Ubc12 by an E2 Binding Domain in NEDD8's E1
Huang, D. T. C., Paydar, A., Zhuang, M., Waddell, M. B., Holton, J. M., & Schulman, B. A. (2005) · Molecular Cell · doi:10.1016/j.molcel.2004.12.020 · Cited by 202 · see citing works
Self-citationMahrour, N., Redwine, W. B., Florens, L., Swanson, S. K., Martin-Brown, S., Bradford, W. D., Staehling-Hampton, K., Washburn, M. P., Conaway, R. C., & Conaway, J. W. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m706987200 · Cited by 196 · see citing works
The conserved protein DCN-1/Dcn1p is required for cullin neddylation in C. elegans and S. cerevisiae
Kurz, T., Özlü, N., Rudolf, F., O’Rourke, S. M., Luke, B., Hofmann, K., Hyman, A. A., Bowerman, B. A., & Peter, M. (2005) · Nature · doi:10.1038/nature03662 · Cited by 188 · see citing works
Ribosomal proteins are targets for the NEDD8 pathway
Xirodimas, D. P., Sundqvist, A., Nakamura, A., Shen, L., Botting, C. H., & Hay, R. T. (2008) · EMBO Reports · doi:10.1038/embor.2008.10 · Cited by 175 · see citing works
Role of the Arabidopsis RING-H2 Protein RBX1 in RUB Modification and SCF Function
Gray, W. M., Hellmann, H. A., Dharmasiri, S., & Estelle, M. A. (2002) · The Plant Cell · doi:10.1105/tpc.003178 · Cited by 173 · see citing works
A Targeted Proteomic Analysis of the Ubiquitin-Like Modifier Nedd8 and Associated Proteins
Jones, J. A., Wu, K. K.-Y., Yang, Y., Guerrero, C., Nillegoda, N. B., Pan, Z., & Huang, L. (2008) · Journal of Proteome Research · doi:10.1021/pr700749v · Cited by 164 · see citing works
Morimoto, M., Nishida, T., Honda, R., & Yasuda, H. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2576 · Cited by 134 · see citing works
Bornstein, G., Ganoth, D., & Hershko, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603921103 · Cited by 127 · see citing works
Sakata, E., Yamaguchi, Y., Miyauchi, Y., Iwaï, K., Chiba, T., Saeki, Y., Matsuda, N., Tanaka, K., & Kato, K. (2007) · Nature Structural & Molecular Biology · doi:10.1038/nsmb1191 · Cited by 114 · see citing works
Capili, A. D., & Lima, C. D. (2007) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2007.08.018 · Cited by 109 · see citing works
Du, F., Navarro, F., Xia, Z., Tasaki, T., & Varshavsky, A. J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172527399 · Cited by 106 · see citing works
Structural Basis of Cellulosome Efficiency Explored by Small Angle X-ray Scattering
Hammel, M., Fierobe, H., Czjzek, M., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503168200 · Cited by 100 · see citing works
Self-citationNedd8-modification of Cul1 is promoted by Roc1 as a Nedd8-E3 ligase and regulates its stability
Morimoto, M., Nishida, T., Nagayama, Y., & Yasuda, H. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)03051-6 · Cited by 98 · see citing works
Wu, K. K.-Y., Chen, A., Tan, P., & Pan, Z. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108008200 · Cited by 82 · see citing works
Amir, R. E., Iwaï, K., & Ciechanover, A. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200967200 · Cited by 75 · see citing works
Huang, D. T. C., Zhuang, M., Ayrault, O., et al. (2008) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1387 · Cited by 61 · see citing works
Hammel, M., Němeček, D., Keightley, J. A., Thomas, G. J., & Geisbrecht, B. V. (2007) · Protein Science · doi:10.1110/ps.073170807 · Cited by 36 · see citing works
Self-citationGenome‐Wide Surveys for Phosphorylation‐Dependent Substrates of SCF Ubiquitin Ligases
Tang, X., Orlicky, S. M., Liu, Q., Willems, A. R., Sicheri, F., & Tyers, M. (2005) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(05)99030-7 · Cited by 33 · see citing works
Laplaza, J. M., Bostick, M. L., Scholes, D. T., Curcio, M. J., & Callis, J. (2004) · Biochemical Journal · doi:10.1042/bj20030755 · Cited by 30 · see citing works
Protein–protein interactions regulate Ubl conjugation
Knipscheer, P., & Sixma, T. K. (2007) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2007.09.001 · Cited by 24 · see citing works
Scaglione, K. M., Bansal, P. K., Deffenbaugh, A. E., Kiss, A., Moore, J. M., Korolev, S., Cocklin, R., Goebl, M. G., Kitagawa, K., & Skowyra, D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01555-06 · Cited by 19 · see citing works
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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
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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
Ubiquitin ligases: structure, function, and regulation
Zheng, N., & Shabek, N. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014922 · Cited by 1,499 · see citing works
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Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works
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Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242 · see citing works
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Ye, Y., & Rape, M. (2009) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2780 · Cited by 989 · see citing works
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Petzold, G., Fischer, E. S., & Thomä, N. H. (2016) · Nature · doi:10.1038/nature16979 · Cited by 620 · see citing works
Zhuang, M., Calabrese, M. F., Liu, J., Waddell, M. B., Nourse, A., Hammel, M., Miller, D. J., Walden, H., Duda, D. M., Seyedin, S. N., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.022 · Cited by 486 · see citing works
Self-citationThe Molecular Basis of CRL4DDB2/CSA Ubiquitin Ligase Architecture, Targeting, and Activation
Fischer, E. S., Scrima, A., Böhm, K., Matsumoto, S., Lingaraju, G. M., Faty, M., Yasuda, T., Cavadini, S., Wakasugi, M., Hanaoka, F., et al. (2011) · Cell · doi:10.1016/j.cell.2011.10.035 · Cited by 460 · see citing works
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Liau, N. P. D., Laktyushin, A., Lucet, I. S., Murphy, J. M., Yao, S., Whitlock, E., Callaghan, K., Nicola, N. A., Kershaw, N. J., & Babon, J. J. (2018) · Nature Communications · doi:10.1038/s41467-018-04013-1 · Cited by 456 · see citing works
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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
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Canning, P., Cooper, C. D. O., Krojer, T., Murray, J. W., Pike, A. C. W., Chaikuad, A., Keates, T., Thangaratnarajah, C., Hojzan, V., Marsden, B. D., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.437996 · Cited by 284 · see citing works
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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
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Soucy, T. A., Dick, L. R., Smith, P. G., Milhollen, M. A., & Brownell, J. E. (2010) · Genes & Cancer · doi:10.1177/1947601910382898 · Cited by 225 · see citing works
Dynamic Allostery: Linkers Are Not Merely Flexible
Ma, B., Tsai, C.-J., Haliloğlu, T., & Nussinov, R. (2011) · Structure · doi:10.1016/j.str.2011.06.002 · Cited by 222 · see citing works
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Self-citationScott, 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
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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
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Calderon-Villalobos, L. I., Tan, X., Zheng, N., & Estelle, M. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005546 · Cited by 177 · see citing works
Protein neddylation and its role in health and diseases
Zhang, S., Yu, Q., Li, Z., Zhao, Y., & Sun, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01800-9 · Cited by 171 · see citing works
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Starostina, N. G., & Kipreos, E. T. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.10.004 · Cited by 147 · see citing works
Priming and Extending: A UbcH5/Cdc34 E2 Handoff Mechanism for Polyubiquitination on a SCF Substrate
Wu, K., Kovacev, J., & Pan, Z.-Q. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.02.025 · Cited by 126 · see citing works
Sievers, Q. L., Gasser, J. A., Cowley, G. S., Fischer, E. S., & Ebert, B. L. (2018) · Blood · doi:10.1182/blood-2018-01-821769 · Cited by 124 · see citing works
Snapshots and ensembles of BTK and cIAP1 protein degrader ternary complexes
Schiemer, J., Horst, R., Meng, Y., Montgomery, J. I., Xu, Y., Feng, X., Borzilleri, K., Uccello, D. P., Leverett, C., Brown, S., et al. (2021) · Nature Chemical Biology · doi:10.1038/s41589-020-00686-2 · Cited by 113 · 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
Bai, N., Riching, K. M., Makaju, A., Wu, H., Acker, T. M., Ou, S.-C., Zhang, Y., Shen, X., Bulloch, D. N., Rui, H., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101653 · Cited by 77 · see citing works
Monomeric Targeted Protein Degraders
Hanan, E. J., Liang, J., Wang, X., Blake, R. A., Blaquiere, N., & Staben, S. T. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00093 · Cited by 69 · see citing works
Structural Basis for Recruitment of DAPK1 to the KLHL20 E3 Ligase
Chen, Z., Picaud, S., Filippakopoulos, P., D'Angiolella, V., & Bullock, A. N. (2019) · Structure · doi:10.1016/j.str.2019.06.005 · Cited by 37 · see citing works
Molecular Architecture of the Ankyrin SOCS Box Family of Cul5-Dependent E3 Ubiquitin Ligases
Muniz, J. R. C., Guo, K., Kershaw, N. J., Ayinampudi, V., von Delft, F., Babon, J. J., & Bullock, A. N. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.06.015 · Cited by 34 · see citing works
Patil, A., Manzano, M., & Gottwein, E. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019031732 · Cited by 29 · see citing works
Chen, Z., Chi, G., Balo, T., Chen, X., Montes, B. R., Clifford, S. C., D’Angiolella, V., Szabo, T., Kiss, A., Novak, T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58350-z · Cited by 10 · see citing works
- Authors
- Duda, D. M., Borg, L. A., Scott, D. C., Hunt, H. W., Hammel, M., & Schulman, B. A.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Lawrence Berkeley National Laboratory (US)
- Corresponding author
- Schulman, Brenda A.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 134
- Issue
- 6
- Pages
- 995-1006
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2628631
- OpenAlex
- W2140219059
- Cited by
- 767
- References
- 63
- Citations by year
- 2026: 29 · 2025: 30 · 2024: 45 · 2023: 31 · 2022: 30 · 2021: 51 · 2020: 60 · 2019: 39 · 2018: 31 · 2017: 41 · 2016: 43 · 2015: 45 · 2014: 41 · 2013: 62 · 2012: 48
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1780 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (P30CA021765)
- National Institute of General Medical Sciences (R01GM069530)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- NEDD8, cullin-RING ligases, CAND1, RBX1, RING domain, E3 ubiquitin ligase, ubiquitination, conformational change, polyubiquitination, crystal structure, small-angle X-ray scattering
- MeSH terms
- NEDD8 Protein, Binding Sites, Humans, Models, Molecular, Transcription Factors, Ubiquitins, Protein Structure, Tertiary, Crystallography, X-Ray, Cullin Proteins, Ubiquitination
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