Co-adaptor driven assembly of a CUL3 E3 ligase complex.

Cullin-RING E3 ligases (CRLs) are essential ubiquitylation enzymes that combine a catalytic core built around cullin scaffolds with ?300 exchangeable substrate adaptors. To ensure robust signal transduction, cells must constantly form new CRLs by pairing substrate-bound adaptors with their cullins, but how this occurs at the right time and place ...
is still poorly understood. Here, we show that formation of individual CRL complexes is a tightly regulated process. Using CUL3KLHL12 as a model, we found that its co-adaptor PEF1-ALG2 initiates CRL3 formation by releasing KLHL12 from an assembly inhibitor at the endoplasmic reticulum, before co-adaptor monoubiquitylation stabilizes the enzyme for substrate modification. As the co-adaptor also helps recruit substrates, its role in CRL assembly couples target recognition to ubiquitylation. We propose that regulators dedicated to specific CRLs, such as assembly inhibitors or co-adaptors, cooperate with target-agnostic adaptor exchange mechanisms to establish E3 ligase complexes that control metazoan development.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Calcium-Binding Proteins, Cullin Proteins, HEK293 Cells, Humans, Mannosyltransferases, Membrane Proteins, Protein Binding, Protein Interaction Domains and Motifs, Protein Stability, Ubiquitin Thiolesterase, Ubiquitination
Mol Cell
Date: Dec. 03, 2021
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