Destined for destruction: The role of methionine aminopeptidases and plant cysteine oxidases in N-degron formation.

The cysteine/arginine (Cys/Arg) branch of the N-degron pathway controls the stability of certain proteins with methionine (Met)-Cys N-termini, initiated by Met cleavage and Cys oxidation. In seeding plants, target proteins include the Group VII Ethylene Response Factors, which initiate adaptive responses to low oxygen (hypoxic) stress, as well as Vernalization 2 (VRN2) and Little Zipper 2 (ZPR2), which are involved in responses to endogenous developmental hypoxia. It is essential that these target proteins are only degraded by the N-degron pathway under the appropriate physiological conditions. Modification of their N-termini is under enzymatic control by Met Aminopeptidases (MetAPs) and Plant Cysteine Oxidases (PCOs); therefore, the substrate-binding requirements and catalytic effectiveness of these enzymes are important for defining which Met-Cys-initiating proteins are degraded. Physiological conditions can also impact the activity of these enzymes, and the well-characterized oxygen sensitivity of the PCOs ensures target proteins are stabilized in hypoxia. In this review we compile the functional and structural properties of MetAPs and PCOs, including their interactions with substrates. We also consider the evolution of MetAPs and PCOs through the plant kingdom to highlight their important role in controlling the initial steps of this branch of the N-degron pathway.