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Biological role

The presence of an unknown microbial cell active the transcription of the defensin-α-1 gene in the human neutrophil. When the RNAm is translated defensins-α-1 are not active. They became active in the Golgi apparatus, in which they are biologically cleaved. Then they are stock in the azurophil granule lumen. After the exocytosis, two defensins-α-1 create a dimere, which'll attack the membran of the microbial cell, by the formation of channel. This channels destabilize the membrane, which causes the destruction of the unknown microbial cell. This mecanism is sum up in the following picture.^[3]

Structure

Monomere structure

Defensin-α-1 peptides are cationic antimicrobial peptides that are synthesized in vivo as inactive precursors.
Activation requires proteolytic excision of their anionic N-terminal inhibitory pro-peptide. The pro-peptide also specifically interacts with and inhibits the antimicrobial activity of the defensin-α-1 intermolecularly.^[5]
The active mature defensin-α-1 peptides consists of 29–35 amino acid residues with a molecular mass of 3–5 kDa.
The primary structure shows highly conserved residues, which are indispensable for the structural stability of the peptides. Among them are six invariant cysteine residues, necessary for the typical defensin-α-1 intramolecular disulphide-bond connectivity :

Defensin-Alpha-1 cysteine connectivities.[6].

We can observe this bridge on the following figure. There are two charged amino acid residues, , forming a conserved salt bridge, and , which constitutes a signature structural motif which is essential for correct folding.

Each defensin monomer consists of three strands of antiparallel β-sheet incorporating 60% of the residues. Two β-turns and three disulfide bonds add further restrictions to the conformational freedom of the monomer.^[7].

Dimere structure

The dimere is formed by joining identical β-strands of the two monomers together to create a symmetrical six-stranded P-sheet. This extended β-sheet twists and curls to form a basket-shaped structure that has a small solvent-accessible channel passing through it. The base of the basket is hydrophobic while the top, which contains the N- and C-terminal domains of the two defensin monomers, is polar. This dimer-of-dimers may be an essential feature of defensins’interaction with membranes.^[8]

Binding with the cell membrane

The interaction of defensin-α-1 with cell membranes involves single dimer binding electrostatically to the cell surface. In fact, the hydrophobic basket bottom of the defensin-α-1 dimer is inserted into the the hydrocarbon layer of one lipid monolayer while the polar group of the basket top and the maintain contact with the headgroup and aqueaus phase. Two dimers created a channel. The dimers can work together and create big channels like the following picture. The are in the basket bottom.^[9].]]

Creation of big channels.[10]

Example

DEF are known to play a role in the in the initiation of innate immune responses to some microbial pathogens. They are antimicrobial peptides of innate immunity functioning by non-specific binding to anionic phospholipids in bacterial membranes. For example defensins-α-1 have a role against the bacteria Trypanosoma cruzi.
^[11].Trypanosoma cruzy or Cruzy debilitats Chagas disease, which affects millions of people and products significant morbidity and mortality. The defensine-α-1 are secreted by the HCT116 cells (which are Paneth cells), when they are infect by Cruzy. They reduces the infection making damage of the flagella structure. This damage inhibit parasite motility and reduce cellular infection. This reaction is introduce in the following drawing.

Defensins-α-1 pathway.

References

1. ↑ http://www.ncbi.nlm.nih.gov/gene/1667
2. ↑ Abraham L. Kierszenbaum. Histologie et biologie cellulaire: Une introduction à l'anatomie pathologique 2002
3. ↑ http://www.reactome.org/PathwayBrowser/#DIAGRAM=1461973&PATH=168256,168249
4. ↑ http://www.reactome.org/PathwayBrowser/#DIAGRAM=1461973&PATH=168256,168249
5. ↑ www.ncbi.nlm.nih.gov/pmc/articles/PMC2754386/ )
6. ↑ Stephen H Wile, William C Wimley and Michael E Selsted. Structure, function, and membrane integration of defensins. Current Opinion in Structural Biology 1995. University of California, Irvine, USA
7. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2049026/
8. ↑ Gary Fujii, Michael E.Selsted, David Eisenberg. Defensins promote fusion and lysis of negatively charged membranes. Protein Science. 1993. Cambridge University.
9. ↑ Stephen H Wile, William C Wimley and Michael E Selsted. Structure, function, and membrane integration of defensins. Current Opinion in Structural Biology 1995. University of California, Irvine, USA
10. ↑ Gary Fujii, Michael E.Selsted, David Eisenberg. Defensins promote fusion and lysis of negatively charged membranes. Protein Science. 1993. Cambridge University.
11. ↑ http://iai.asm.org/content/81/11/4139.full/ref

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