Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly

Daniel Horn-Ghetko, David T. Krist, J. Rajan Prabu, Kheewoong Baek, Monique P. C. Mulder, Maren Klügel, Daniel C. Scott, Huib Ovaa, Gary Kleiger and Brenda A. Schulman ()
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Daniel Horn-Ghetko: Max Planck Institute of Biochemistry
David T. Krist: Max Planck Institute of Biochemistry
J. Rajan Prabu: Max Planck Institute of Biochemistry
Kheewoong Baek: Max Planck Institute of Biochemistry
Monique P. C. Mulder: Leiden University Medical Centre
Maren Klügel: Max Planck Institute of Biochemistry
Daniel C. Scott: St Jude Children’s Research Hospital
Huib Ovaa: Leiden University Medical Centre
Gary Kleiger: University of Nevada, Las Vegas
Brenda A. Schulman: Max Planck Institute of Biochemistry

Nature, 2021, vol. 590, issue 7847, 671-676

Abstract: Abstract E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates1,2. However, rather than functioning individually, many neddylated cullin–RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family—which together account for nearly half of all ubiquitin ligases in humans—form E3–E3 super-assemblies3–7. Here, by studying CRLs in the SKP1–CUL1–F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3–E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3–E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3–E3 super-assembly may therefore underlie widespread ubiquitylation.

Date: 2021
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DOI: 10.1038/s41586-021-03197-9

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