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According to a recent study, the N-terminal acetylation of the regulator glycoprotein and N-end rule degradation leads to hypertension. Blood pressure is regulated through the G-protein linked signaling pathway that causes vasoconstriction. Regulatory proteins such as Ras2 has been found to go through the N-terminal acetylation followed by the N-end rule mediated degradation.
N-terminal acetylation is one of the post-translational modifications of proteins in the eukaryotes catalyzed by the N-terminal acetyltransferase. There are six types of N-terminal acetyltransferase with numerous functions like modulation of the subcellular localization, protein-protein interaction, etc. and it has also been found that the N-terminal acetyl group decreases the half-life of the protein.
The N-terminal acetylated group is called Ac/N-degron and it can be recognized by an Ac/N-recognin, Doa10. It is an E3 ubiquitin ligase enzyme that targets Ac/N-degron for proteasomal degradation. While proteins that don’t have Ac/N-degrons are recognized and degraded by the Arg/N-end rule pathway.
There are more proteins with N-terminal acetylation and can be cotranslationally targeted for proteasomal degradation. However, their degradation is conditional. In some glycoproteins, N-terminal acetylated moiety (Ac/N-degron) is shielded by a complex structure of the protein and, therefore, Ac/N-degron is not recognized by the Ac/N-recognin increasing the half-life of the glycoprotein.
Rgs2 is a regulator of G-protein linked signaling pathway in mammals where it is subjected to degradation by Ac/N-recognin Teb4. The result reveals that the two mutant Rgs2 N-terminals ML-Rgs2 and MR-Rgs2 are associated with hypertension. These mutants are present in the lower levels than those of the wild types of Rgs2 N-terminals (MQ-Rgs2).
This is because mutant Rgs2 N-terminals are rapidly degraded in the proteasome by either Ac/N-end rule pathway or both the Ac/N-end and Arg/N-end pathway. In this way, the N-terminal acetyl group links the molecular level of the Ac/N-end rule mediated degradation of G-proteins to the cellular and physiological levels and, therefore, N-terminal acetylated and unacetylated forms of the same protein can be targeted.
Reference: Trends in Biochemical Sciences
Article DOI: 10.1016/j.tibs.2015.05.003