Plasticity in structure and interactions is critical for the action of indolicidin, an antibacterial peptide of innate immune origin

The comparative analysis of two cationic antibacterial peptides of the cathelicidin family—indolicidin and tritrypticin—enabled addressing the structural features critical for the mechanism of indolicidin activity. Functional behavior of retro‐indolicidin was found to be identical to that of native indolicidin. It is apparent that the gross conformational propensities associated with retro‐peptides resemble those of the native sequences, suggesting that native and retro‐peptides can have similar structures. Both the native and the retro‐indolicidin show identical affinities while binding to endotoxin, the initial event associated with the antibacterial activity of cationic peptide antibiotics. The indolicidin–endotoxin binding was modeled by docking the indolicidin molecule in the endotoxin structure. The conformational flexibility associated with the indolicidin residues, as well as that of the fatty acid chains of endotoxin combined with the relatively strong structural interactions, such as ionic and hydrophobic, provide the basis for the endotoxin–peptide recognition. Thus, the key feature of the recognition between the cationic antibacterial peptides and endotoxin is the plasticity of molecular interactions, which may have been designed for the purpose of maintaining activity against a broad range of organisms, a hallmark of primitive host defense.

[1]  N. Greenspan,et al.  All-D peptides recognized by an anti-carbohydrate antibody identified from a positional scanning library. , 1998, Journal of molecular biology.

[2]  G. Cohen,et al.  Interactions of protein antigens with antibodies. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[3]  K. Rao,et al.  Maturation of an antibody response is governed by modulations in flexibility of the antigen-combining site. , 2000, Immunity.

[4]  R. Hancock,et al.  Cationic bactericidal peptides. , 1995, Advances in microbial physiology.

[5]  A G Leslie,et al.  Molecular architecture of the rotary motor in ATP synthase. , 1999, Science.

[6]  R. B. Merrifield,et al.  Retro and retroenantio analogs of cecropin-melittin hybrids. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Wayne L. Smith,et al.  Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils. , 1992, The Journal of biological chemistry.

[8]  J. Cavaillon,et al.  A novel granulocyte-derived peptide with lipopolysaccharide-neutralizing activity. , 1994, Journal of immunology.

[9]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[10]  R. Woody.  Chapter 2 – Circular Dichroism of Peptides , 1985 .

[11]  M. Zasloff.  Antimicrobial peptides of multicellular organisms , 2002, Nature.

[12]  A. Goldberg,et al.  Inhibition of ubiquitin-proteasome pathway–mediated IκBα degradation by a naturally occurring antibacterial peptide , 2000 .

[13]  H. G. Boman,et al.  Antibacterial peptides: Key components needed in immunity , 1991, Cell.

[14]  R L Stanfield,et al.  Antibody-antigen interactions: new structures and new conformational changes. , 1994, Current opinion in structural biology.

[15]  H. G. Boman,et al.  Mechanisms of action on Escherichia coli of cecropin P1 and PR-39, two antibacterial peptides from pig intestine , 1993, Infection and immunity.

[16]  M. Klagsbrun,et al.  Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. H. Gudmundsson,et al.  Neutrophil antibacterial peptides, multifunctional effector molecules in the mammalian immune system. , 1999, Journal of immunological methods.

[18]  K. Diederichs,et al.  A conserved structural motif for lipopolysaccharide recognition by procaryotic and eucaryotic proteins. , 2000, Structure.

[19]  R. B. Merrifield,et al.  Synthesis and study of normal, enantio, retro, and retroenantio isomers of cecropin A-melittin hybrids, their end group effects and selective enzyme inactivation. , 2009, The journal of peptide research : official journal of the American Peptide Society.

[20]  R. Hancock,et al.  Structure of the bovine antimicrobial peptide indolicidin bound to dodecylphosphocholine and sodium dodecyl sulfate micelles. , 2000, Biochemistry.

[21]  P. Tempst,et al.  Apidaecin-type peptide antibiotics function through a non-poreforming mechanism involving stereospecificity. , 1994, Biochemical and biophysical research communications.

[22]  Domenico Romeo,et al.  Cathelicidins: a novel protein family with a common proregion and a variable C‐terminal antimicrobial domain , 1995, FEBS letters.

[23]  R. Hancock,et al.  Interaction of polycationic antibiotics with Pseudomonas aeruginosa lipopolysaccharide and lipid A studied by using dansyl-polymyxin , 1986, Antimicrobial Agents and Chemotherapy.

[24]  J. V. van Strijp,et al.  Affinities of different proteins and peptides for lipopolysaccharide as determined by biosensor technology. , 1998, Biochemical and biophysical research communications.

[25]  R. Hancock.  Peptide antibiotics , 1997, The Lancet.

[26]  N. Surolia,et al.  Kinetics and Mechanism of the Recognition of Endotoxin by Polymyxin B , 1998 .

[27]  D. Salunke,et al.  Structure-Function Analysis of Tritrypticin, an Antibacterial Peptide of Innate Immune Origin* , 1999, The Journal of Biological Chemistry.

[28]  M. Teuber,et al.  Action of Polymyxin B on Bacterial Membranes: Morphological Changes in the Cytoplasm and in the Outer Membrane of Salmonella typhimurium and Escherichia coli B , 1975, Antimicrobial Agents and Chemotherapy.

[29]  Y. Shai.  Molecular recognition between membrane-spanning polypeptides. , 1995, Trends in biochemical sciences.

[30]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[31]  E. Di Cera,et al.  Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. , 1997, Science.

[32]  R. Hancock,et al.  Mode of Action of the Antimicrobial Peptide Indolicidin* , 1996, The Journal of Biological Chemistry.

[33]  S. Pillai,et al.  Innate immunity. , 1996, Current opinion in immunology.

[34]  R. Stroud,et al.  Crystal Structure of the Signal Sequence Binding Subunit of the Signal Recognition Particle , 1998, Cell.

[35]  P. Sigler,et al.  The Crystal Structure of a GroEL/Peptide Complex Plasticity as a Basis for Substrate Diversity , 1999, Cell.