Conformation and activity of delta-lysin and its analogs.
Delta-Lysin is a 26-residue hemolytic peptide secreted by Staphylococcus aureus. Unlike the bee venom peptide melittin, delta-lysin does not exhibit antibacterial activity. We have synthesized delta-lysin and several analogs wherein the N-terminal residues of the toxin were sequentially deleted. The toxin has three aspartic acids, four lysines and no prolines. Analogs were also generated in which all the aspartic acids were replaced with lysines. A proline residue was introduced in the native sequences as well as in the analogs where aspartic acids were replaced with lysines. We observed that 20- and 22-residue peptides corresponding to residues 7-26 and 5-26 of delta-lysin, respectively, had greater hemolytic activity than the parent peptide. These shorter peptides, unlike delta-lysin, did not self-associate to adopt alpha-helical conformation in water, at lytic concentrations. Introduction of proline or substitution of aspartic acids by lysines resulted in loss in propensity to adopt helical conformation in water. When proline was introduced in the peptides corresponding to the native toxin sequence, loss of hemolytic activity was observed. Substitution of all the aspartic acids with lysines resulted in enhanced hemolytic activity in all the analogs. However, when both proline and aspartic acid to lysine changes were made, only antibacterial activity was observed in the shorter peptides. Our investigations on delta-lysin and its analogs provide insights into the positioning of anionic, cationic residues and proline in determining hemolytic and antibacterial activities.
Dhople
Vishnu M
VM
Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
Nagaraj
Ramakrishnan
R
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002942:Circular Dichroism; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D006168:Guinea Pigs; D006460:Hemolysin Proteins / Q000494:pharmacology*; D008239:Lysine / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010455:Peptides; D011392:Proline / Q000378:metabolism; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006460:Hemolysin Proteins; D010455:Peptides; C025994:delta hemolysin protein, Staphylococcus aureus; D011392:Proline; D008239:Lysine