Mangano, K., Klepacki, D., Ohanmu, I., Baliga, C., Huang, W., Brakel, A., Krizsan, A., Polikanov, Y.S., Hoffmann, R., Vázquez-Laslop, N., Mankin, A.S. (2023). Inhibition of translation termination by the antimicrobial peptide Drosocin.  Nat. Chem. Biol. 19(9): 1082--1090.

FBrf0257454

Research paper

The proline-rich antimicrobial peptide (PrAMP) Drosocin (Dro) from fruit flies shows sequence similarity to other PrAMPs that bind to the ribosome and inhibit protein synthesis by varying mechanisms. The target and mechanism of action of Dro, however, remain unknown. Here we show that Dro arrests ribosomes at stop codons, probably sequestering class 1 release factors associated with the ribosome. This mode of action is comparable to that of apidaecin (Api) from honeybees, making Dro the second member of the type II PrAMP class. Nonetheless, analysis of a comprehensive library of endogenously expressed Dro mutants shows that the interactions of Dro and Api with the target are markedly distinct. While only a few C-terminal amino acids of Api are critical for binding, the interaction of Dro with the ribosome relies on multiple amino acid residues distributed throughout the PrAMP. Single-residue substitutions can substantially enhance the on-target activity of Dro.

PMC10757563 (PMC) (EuropePMC)