Abstract：
:RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes.
journal_name
Mol Celljournal_title
Molecular cellauthors
Gabrielsen M,Buetow L,Nakasone MA,Ahmed SF,Sibbet GJ,Smith BO,Zhang W,Sidhu SS,Huang DTdoi
10.1016/j.molcel.2017.09.027subject
Has Abstractpub_date
2017-10-19 00:00:00pages
456-470.e10issue
2eissn
1097-2765issn
1097-4164pii
S1097-2765(17)30705-0journal_volume
68pub_type
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