C-degron mimicry confers E3 ligase selectivity

E3 ubiquitin ligases are a part of the ubiquitin–proteasome system and act by transferring ubiquitin to substrate proteins, ultimately leading to their degradation. A subset of E3 ubiquitin ligases, termed ‘C-degron’ E3 ligases, recruit substrate proteins by recognition of C-terminal destabilizing motifs (C-degrons). These sequences are also found in other proteins, including ubiquitin and ubiquitin-like (UBL) proteins, that are not targeted for ubiquitylation, raising the question of how E3 ligases discriminate these from bona fide substrates. Scott et al. now show that C-degron mimicry by the C-terminus of the human E3 ligase CRL2KLHDC2 results in autoinhibition of the enzyme and promotes substrate selectivity.

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