Methyl-Lysine-Dependent Control of Protein Lifetime Through Lysine-Node Crosstalk and Reader-Coupled Degradation

The half-life of proteins is determined by the "information" carried within specific regions of the protein. Lysine methylation is an emerging post-translational modification that can act at the decision node. In contrast to the charge-neutralizing effects of lysine acylation, methylation maintains the positive charge of the lysine residue, allowing for the presence of multiple methylation states (Kme1/2/3). This property enables the "reading" of the methylation state by "methyl lysine readers." Although the methyl group is chemically stable, the methylation is enzymatically reversible by lysine demethylases. In this review, we conceptualize the "methyl lysine" as an "information"-containing "signal" at the decision node. The "information" is composed of the interplay between the "competition" among the same site modifications, the "methylation-dependent degron" or "methyl degrons," the "steric blockade" or "methyl shields," and the "changes in spatial routing" or "methyl routing cues." In this review, we discuss the emerging evidence within these three types of functional methyl lysine.