Loop Replacement Enhances the Ancestral Antibacterial Function of a Bifunctional Scorpion Toxin

• Published in: Toxins 2018-06, Vol.10 (6), p.227
• Main Authors: Zhang, Shangfei, Gao, Bin, Wang, Xueli, Zhu, Shunyi
• Format: Article
• Language: English
• Subjects: Amino acids; Antibacterial activity; Antibiotic resistance; Antibiotics; Antimicrobial agents; Bacteria; Channels; Chromatography; defensin; Defensins; E coli; Evolution; Genomes; Gram-positive bacteria; Hypotheses; loop; MeuTXKα3; Neurotoxins; Opportunist infection; Peptides; Phylogenetics; Potassium; Protein engineering; Proteins; scaffold; scorpion K+ channel toxin; Toxins; Venom
• ISSN: 2072-6651; 2072-6651
• DOI: 10.3390/toxins10060227

On the basis of the evolutionary relationship between scorpion toxins targeting K⁺ channels (KTxs) and antibacterial defensins (Zhu S., Peigneur S., Gao B., Umetsu Y., Ohki S., Tytgat J. Experimental conversion of a defensin into a neurotoxin: Implications for origin of toxic function. Mol. Biol. Evol. 2014, 31, 546⁻559), we performed protein engineering experiments to modify a bifunctional KTx (i.e., weak inhibitory activities on both K⁺ channels and bacteria) via substituting its carboxyl loop with the structurally equivalent loop of contemporary defensins. As expected, the engineered peptide (named MeuTXKα3-KFGGI) remarkably improved the antibacterial activity, particularly on some Gram-positive bacteria, including several antibiotic-resistant opportunistic pathogens. Compared with the unmodified toxin, its antibacterial spectrum also enlarged. Our work provides a new method to enhance the antibacterial activity of bifunctional scorpion venom peptides, which might be useful in engineering other proteins with an ancestral activity.