Titivated for destruction: the methyl degron

Abstract

In this issue, Lee et al. (2012) demonstrate that the degradation of RORα is regulated by the EZH2-DCAF1/DDB1/CUL4 proteasome axis, thus identifying protein methylation as a posttranslational modification that can orchestrate protein destruction through a motif termed the "methyl degron."

Figure 1. Degrons that facilitate targeting of the Ub-proteasome system

Short-lived proteins in eukaryotes are recognized and degraded by Ub-proteasome system, a process that is coordinated by consecutive enzymatic steps (ubiquitin activation by E1; conjugation by E2; and ligation by E3) and culminates in the transfer of ubiquitin (Ub) to a lysine residue within the substrate. Ub can be added either individually or in chains. The specificity of this system is achieved by substrate recognition modules that form part of E3 complexes (the family of HECT E3s are not included here). The UBR Box in UBR proteins recognize specific N-terminal residues (N-degron); F-Box proteins (FBPs) form part of the CUL1/SKP1 complex and harbor either WD40 domains or Leucine-rich regions that recognize phosphorylated serine or threonine residues (Phospho-degron); the β-domain of VHL protein in CUL2/RBX1 complex recognizes proline residues that are hydroxylated (Hydroxylated-degron); and the Chromo domain of DCAF1 in CUL4/DDB1 complex recognizes mono-methylated lysine motifs (Methyl-degron).