How C-Terminal Carboxyamidation Alters the Biological Activity of Peptides from the Venom of the Eumenine Solitary Wasp
详细信息 查看全文
- 作者：Maurí ; cio L. Sforç ; a ; Sé ; rgio Oyama ; Jr. ; Fernanda Canduri ; Carla C. B. Lorenzi ; Thelma A. Pertinhez ; Katsuhiro Konno ; Bibiana M. Souza ; Má ; rio S. Palma ; J. Ruggiero Neto ; Walt
- 刊名：Biochemistry
- 出版年：2004
- 出版时间：May 18, 2004
- 年：2004
- 卷：43
- 期：19
- 页码：5608 - 5617
- 全文大小：340K
- 年卷期：v.43,no.19(May 18, 2004)
- ISSN：1520-4995
文摘
Inflammatory peptides display different types of post-transcriptional modifications, such asC-terminal amidation, that alter their biological activity. Here we describe the structural and moleculardynamics features of the mast cell degranulating peptide, eumenine mastoparan-AF (EMP-AF-NH2), foundin the venom of the solitary wasp, and of its carboxyl-free C-terminal form (EMP-AF-COO-) characterizedby a reduced activity. Circular dichroism indicates that both peptides switch from a random coilconformation in water to a helical structure in TFE and SDS micelles. NMR data, in 30% TFE, revealthat the two peptides fold into an 
-helix spanning most of their length, while they differ in terms ofmolecular rigidity. To understand the origins of the conformational flexibility observed in the case ofEMP-AF-COO-, a 5 ns MD simulation was carried out for each peptide, in an explicit water/TFEenvironment. The results show that the two peptides differ in an H-bond between Leu14 NH2 and thebackbone carbonyl of Ile11. The loss of that H-bond in EMP-AF-COO- leads to a significant modificationof its structural dynamics. In fact, as evidenced by essential dynamics analysis, while EMP-AF-NH2 existsmainly as a rigid structure, EMP-AF-COO- presents two helical stretches that fluctuate in some sort ofindependent fashion. We conclude that the diverse biological activity of the two peptides is not simplydue to the reduction of the net positive charge, as generally suggested, but also to a structural perturbationof the amphipathic -helix that affects their ability to perturb the cell membrane.
-helix spanning most of their length, while they differ in terms ofmolecular rigidity. To understand the origins of the conformational flexibility observed in the case ofEMP-AF-COO-, a 5 ns MD simulation was carried out for each peptide, in an explicit water/TFEenvironment. The results show that the two peptides differ in an H-bond between Leu14 NH2 and thebackbone carbonyl of Ile11. The loss of that H-bond in EMP-AF-COO- leads to a significant modificationof its structural dynamics. In fact, as evidenced by essential dynamics analysis, while EMP-AF-NH2 existsmainly as a rigid structure, EMP-AF-COO- presents two helical stretches that fluctuate in some sort ofindependent fashion. We conclude that the diverse biological activity of the two peptides is not simplydue to the reduction of the net positive charge, as generally suggested, but also to a structural perturbationof the amphipathic -helix that affects their ability to perturb the cell membrane.