Abstract
How RING E3 ligases mediate E2-to-substrate ubiquitin-like protein (UBL) transfer remains unknown. Here we address how the RING E3 RBX1 positions NEDD8's E2 (UBC12) and substrate (CUL1). We find that existing structures are incompatible with CUL1 NEDD8ylation and report a new conformation of RBX1 that places UBC12 adjacent to CUL1. We propose RING domain rotation as a general mechanism for UBL transfer for the largest family of E3s.
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Acknowledgements
This work was supported by American Lebanese Syrian Associated Charities (ALSAC), the St. Jude Cancer Center Core grant, US National Institutes of Health (NIH) grants R01GM069530 to B.A.S. and R01CA082491 to R.W.K. and the Howard Hughes Medical Institute (HHMI). B.A.S. is an Investigator of the HHMI, and M.F.C. is an HHMI postdoctoral fellow of the Damon Runyon Cancer Research Foundation (DRG 2021-9). We thank A. Nourse for analytical ultracentrifugation experiments, J. Monda for experimental assistance and discussions, and D.W. Miller, S. Bozeman, D.J. Miller and J. Bollinger for administrative and computational support. NE-CAT is supported by NIH grant NCRR RR-15301 and the APS by US Department of Energy grant W-31-109-ENG-38.
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M.F.C. designed, performed and analyzed experiments, and wrote the manuscript. D.C.S. designed, performed and analyzed experiments. D.M.D. designed and analyzed experiments. C.R.R.G. designed and performed experiments. R.W.K. designed and analyzed experiments. I.K. designed and performed experiments. B.A.S. advised and assisted on all aspects of the project and wrote the manuscript.
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Calabrese, M., Scott, D., Duda, D. et al. A RING E3–substrate complex poised for ubiquitin-like protein transfer: structural insights into cullin-RING ligases. Nat Struct Mol Biol 18, 947–949 (2011). https://doi.org/10.1038/nsmb.2086
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DOI: https://doi.org/10.1038/nsmb.2086