Sandbox Reserved 1099: Difference between revisions
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The '''trimer''' is formed by '''<scene name='82/829352/Salt_bridges/1'>salt bridges</scene>''' between 3 subunits. These bonds based on the zipper structure are managed again by the negatively (in blue) and positively (in red) charged residues, hence hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be also localized in the bond area neglecting positive amino acids. In total, 96 residues are ionizable which are all facing toward the interior of the tunnel forming <scene name='82/829352/Girdles/1'>five girdles</scene> : I,II,III,II,I as they are alternating negative (in blue) and positive (in red) charges.<ref name="girdles"/> They create a channel with an overall charge of -12 because DCD-1L peptide is -2. | The '''trimer''' is formed by '''<scene name='82/829352/Salt_bridges/1'>salt bridges</scene>''' between 3 subunits. These bonds based on the zipper structure are managed again by the negatively (in blue) and positively (in red) charged residues, hence hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be also localized in the bond area neglecting positive amino acids. In total, 96 residues are ionizable which are all facing toward the interior of the tunnel forming <scene name='82/829352/Girdles/1'>five girdles</scene> : I,II,III,II,I as they are alternating negative (in blue) and positive (in red) charges.<ref name="girdles"/> They create a channel with an overall charge of -12 because DCD-1L peptide is -2. | ||
The amino acids pointing toward the exterior are <scene name='82/829352/Hydrophobic_polar/1'>hydrophobic</scene> (in grey) because they are able to interact with the acyl chain of the membrane. They play a role in the cell membrane insertion.<ref>Van Sang Nguyen, Kang Wei Tan, Karthik Ramesh, Fook Tim Chew & Yu Keung Mok. "Structural basis for the bacterial membrane insertion of dermcidin" Nature Scientific reports 7 : 13923 (2017). https://doi.org/10.1038/s41598-017-13600-z </ref> | The amino acids pointing toward the exterior are <scene name='82/829352/Hydrophobic_polar/1'>hydrophobic</scene> (in grey) because they are able to interact with the acyl chain of the membrane. They play a role in the cell membrane insertion.<ref name="nguyen">Van Sang Nguyen, Kang Wei Tan, Karthik Ramesh, Fook Tim Chew & Yu Keung Mok. "Structural basis for the bacterial membrane insertion of dermcidin" Nature Scientific reports 7 : 13923 (2017). https://doi.org/10.1038/s41598-017-13600-z </ref> | ||
The bonds between monomers allow the formation of 6 <scene name='82/829352/Eyelets/1'>lateral openings</scene> of a diameter of 1 nm (in purple) responsible of ions crossings. The presence of polar residues may have an impact on the selection of ion entry.<ref name="girdles"/> | The bonds between monomers allow the formation of 6 <scene name='82/829352/Eyelets/1'>lateral openings</scene> of a diameter of 1 nm (in purple) responsible of ions crossings. The presence of polar residues may have an impact on the selection of ion entry.<ref name="girdles"/> | ||
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Dermcidin is present in the sweat around 1-10 µg/ml and acts like a regulator of the skin flora. The DCD antimicrobial activity is effective under a specific pH and salt concentrations of the sweat <ref name="novel"/>. | Dermcidin is present in the sweat around 1-10 µg/ml and acts like a regulator of the skin flora. The DCD antimicrobial activity is effective under a specific pH and salt concentrations of the sweat <ref name="novel"/>. | ||
The overall negatively charged DCD-1L is a one amino acid longer DCD-1 and shows beside the antimicrobial activity against [https://en.wikipedia.org/wiki/Escherichia_coli_ ''Escherichia coli''], [https://en.wikipedia.org/wiki/Staphylococcus_aureus_ ''Staphylococcus aureus''] and [https://en.wikipedia.org/wiki/Enterococcus_faecalis_ ''Enterococcus faecalis''] additional high fungicidal activity on [https://en.wikipedia.org/wiki/Candida_albicans_ ''Candida albicans''].<ref name="novel"/> The first three amino acids (SSL) up to the 23th amino acids of DCD-1L is a region which appears to be responsible for the antibacterial activity. The killing of bacteria rises significantly after 2 – 3 hours of incubation which is not driven by a permeabilization of the outer nor inner bacterial membrane.<ref> Steffen, H., Rieg, S., Wiedemann, I., Kalbacher, H., Deeg, M., Sahl, H.-G., Peschel, A., Gotz, F., Garbe, C., Schittek, B., 2006. Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge. Antimicrobial Agents and Chemotherapy 50, 2608–2620. https://doi.org/10.1128/AAC.00181-06 </ref> However, some authors are not in agreement on this with each other<ref name="girdles"/> since it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn<sup>2+</sup>.<ref name="de"> Paulmann, M., Arnold, T., Linke, D., Özdirekcan, S., Kopp, A., Gutsmann, T., Kalbacher, H., Wanke, I., Schuenemann, V.J., Habeck, M., Bürck, J., Ulrich, A.S., Schittek, B., 2012. Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat. J. Biol. Chem. 287, 8434–8443. https://doi.org/10.1074/jbc.M111.332270 </ref> The complex process of forming such a channel starts with a flat approach to the bacterial membrane. Zn<sup>2+</sup> stabilizes the slow formation of oligomeric complexes and coordinates the His38 residue. A break up of the oligomeric complex follows, leading to a membrane insertion and ending with a re-oligomerization so that the channel is formed.<ref> Burian, M., Schittek, B., 2015. The secrets of dermcidin action. International Journal of Medical Microbiology 305, 283–286. https://doi.org/10.1016/j.ijmm.2014.12.012 </ref> | The overall negatively charged DCD-1L is a one amino acid longer DCD-1 and shows beside the antimicrobial activity against [https://en.wikipedia.org/wiki/Escherichia_coli_ ''Escherichia coli''], [https://en.wikipedia.org/wiki/Staphylococcus_aureus_ ''Staphylococcus aureus''] and [https://en.wikipedia.org/wiki/Enterococcus_faecalis_ ''Enterococcus faecalis''] additional high fungicidal activity on [https://en.wikipedia.org/wiki/Candida_albicans_ ''Candida albicans''].<ref name="novel"/> The first three amino acids (SSL) up to the 23th amino acids of DCD-1L is a region which appears to be responsible for the antibacterial activity. The killing of bacteria rises significantly after 2 – 3 hours of incubation which is not driven by a permeabilization of the outer nor inner bacterial membrane.<ref> Steffen, H., Rieg, S., Wiedemann, I., Kalbacher, H., Deeg, M., Sahl, H.-G., Peschel, A., Gotz, F., Garbe, C., Schittek, B., 2006. Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge. Antimicrobial Agents and Chemotherapy 50, 2608–2620. https://doi.org/10.1128/AAC.00181-06 </ref> However, some authors are not in agreement on this with each other<ref name="girdles"/> since it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn<sup>2+</sup>.<ref name="de"> Paulmann, M., Arnold, T., Linke, D., Özdirekcan, S., Kopp, A., Gutsmann, T., Kalbacher, H., Wanke, I., Schuenemann, V.J., Habeck, M., Bürck, J., Ulrich, A.S., Schittek, B., 2012. Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat. J. Biol. Chem. 287, 8434–8443. https://doi.org/10.1074/jbc.M111.332270 </ref> The complex process of forming such a channel starts with a flat approach to the bacterial membrane. Zn<sup>2+</sup> stabilizes the slow formation of oligomeric complexes and coordinates the His38 residue. A break up of the oligomeric complex follows, leading to a membrane insertion and ending with a re-oligomerization so that the channel is formed.<ref> Burian, M., Schittek, B., 2015. The secrets of dermcidin action. International Journal of Medical Microbiology 305, 283–286. https://doi.org/10.1016/j.ijmm.2014.12.012 </ref> Another study found further evidence for the membrane insertion but only of the cationic N-terminus of DCD-1L with K6 and K13 could being involved in the channel formation.<ref name="nguyen"/> | ||
12 DCD-1L-derived peptides by CatD, a carboxypeptidase and an endoprotease are present in human sweat. Some of them have no antimicrobial effect, however, one appears to be more active against ''E. coli'' than DCD-1L. Therefor the antimicrobial defense of humans does not stop at the point of DCD-1L but is more likely modulated by further proteolytic processes (e.g. by CatD) to maintain a healthy innate immune defense on the human skin.<ref name="baechle"/> | 12 DCD-1L-derived peptides by CatD, a carboxypeptidase and an endoprotease are present in human sweat. Some of them have no antimicrobial effect, however, one appears to be more active against ''E. coli'' than DCD-1L. Therefor the antimicrobial defense of humans does not stop at the point of DCD-1L but is more likely modulated by further proteolytic processes (e.g. by CatD) to maintain a healthy innate immune defense on the human skin.<ref name="baechle"/> | ||
