Inhibition of the Arg/N-end rule pathway-mediated proteolysis by dipeptide-mimetic molecules
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Ubr11 in the fission yeast Schizosaccharomyces pombe is an evolutionarily conserved ubiquitin ligase functioning in the Arg/N-end rule pathway, which promotes degradation of substrate proteins via the proteasome. Ubr11 recognizes the N-degron sequence in substrates. The primary N-degron contains a destabilization-inducing N-terminal amino acid, which is either a basic (type 1) or bulky hydrophobic (type 2) residue. Dipeptides are known to inhibit proteolytic degradation via the Arg/N-end rule pathway. Here, I examined the potency of some amino acid- or dipeptide-related molecules in their inhibition of Ubr11/N-end rule-mediated degradation. An amide form of l-arginine and l-tryptophan had weak inhibitory activity for type 1 and type 2 substrates, respectively, although the unmodified amino acid monomer and its carboxymethylated ester were ineffective. Among the naturally occurring dipeptides tested, Lys-Leu and Tyr-Leu showed potent inhibitory activity, but their effect was transient, especially at submillimolar concentrations. l-arginine-β-naphthylamide (Arg-βNA) showed stronger activity than several dipeptides for type 1 substrates, but all Lys-Leu, Tyr-Leu, and Arg-βNA caused growth retardation. The inhibitory activity of the l-phenylalanine carbobenzoxy-hydrazide for type 2 substrates was not very strong, but it prolonged the action of Tyr-Leu at low concentrations and, importantly, did not interfere with cell growth. Apart from their utility, these dipeptidomimetics provide a clue for understanding the determinants of recognition by Ubr ubiquitin ligase and further designing novel inhibitors of the Arg/N-end rule pathway.
KeywordsN-End rule pathway Ubiquitin ligase Ubr protein Dipeptidomimetic S. pombe
This work was financially supported by management expenses grants to Hiroshima University from Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan. I thank Drs. Ichiro Yamashita and Nobukazu Tanaka for their help and discussions.
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Conflict of interest
The author declares that there are no conflicts of interest.
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