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However, some cleavages of the precursor occur probably in sweat to produce different active forms of dermcidin peptide. The most abundant proteolytically processed DCD peptide present in sweat is '''DCD-1L''' (amino acid sequence in bold).  
However, some cleavages of the precursor occur probably in sweat to produce different active forms of dermcidin peptide. The most abundant proteolytically processed DCD peptide present in sweat is '''DCD-1L''' (amino acid sequence in bold).  


DCD-1L is created by proteases in sweat after the first post-secretory processing step consisting to reduce the peptide to the C-terminal thereupon containing 48 residues, from the 63 to the 110 amino acid. And secondly, the [https://www.uniprot.org/uniprot/P07339_ cathepsin D] with 1,10-phenthroline-sensitive carboxypeptidase still not cited in sweat composition yet and an unidentified endoprotease contribute to further processed the DCD-1L C-terminal to produce other derived-peptides (12 have been discovered)<ref name="baechle">Daniel Baechle, Thomas Flad, Alexander Cansier, Heiko Steffen, Birgit Schittek, Jonathan Tolson, Timo Herrmann, Hassan Dihazi􏰀, Alexander Beck, Gerhard A. Mueller􏰀, Margret Mueller, Stefan Stevanovic, Claus Garbe, Claudia A. Mueller, and Hubert Kalbacher. "Cathepsin D Is Present in Human Eccrine Sweat and Involved in the Postsecretory Processing of the Antimicrobial Peptide DCD-1L" J. Biol. Chem. 281, no. 9 (March 3, 2006): 5406-15. https://doi.org/10.1074/jbc.M504670200 </ref>. One of them is DCD-1 which lacks the last leucine.  
DCD-1L is created by proteases in sweat. The first post-secretory processing step consists in reducing the C-terminal of the peptide containing 48 residues, from 63 to 110 amino acids. Then, the [https://www.uniprot.org/uniprot/P07339_ cathepsin D]an protease, with 1,10-phenthroline-sensitive and another unidentified endoprotease contribute to further processed the DCD-1L C-terminal to produce other derived-peptides (12 have been discovered)<ref name="baechle">Daniel Baechle, Thomas Flad, Alexander Cansier, Heiko Steffen, Birgit Schittek, Jonathan Tolson, Timo Herrmann, Hassan Dihazi􏰀, Alexander Beck, Gerhard A. Mueller􏰀, Margret Mueller, Stefan Stevanovic, Claus Garbe, Claudia A. Mueller, and Hubert Kalbacher. "Cathepsin D Is Present in Human Eccrine Sweat and Involved in the Postsecretory Processing of the Antimicrobial Peptide DCD-1L" J. Biol. Chem. 281, no. 9 (March 3, 2006): 5406-15. https://doi.org/10.1074/jbc.M504670200 </ref>. One of them is DCD-1 which lacks the last leucine.  
   
   
== Structural highlights ==
== Structural highlights ==
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===The zinc cofactors===
===The zinc cofactors===


The majority of zinc ions found in sweat particularly are divalent zinc ions. Their presence is fundamental since the lack of these ions results in the inability of dermcidin to form a channel. The high permeability for water and conductance of the channel is also established by Zn<sup>2+</sup>.<ref name="girdles"/>  
Most zinc ions found in sweat are divalent zinc ions (they have two charges and thus can create two bonds). Their presence is fundamental since the lack of these ions results in the inability of dermcidin to form a channel. The high permeability for water and conductance of the channel is also established by Zn<sup>2+</sup>.<ref name="girdles"/>  


== Antimicrobial activity ==
== Antimicrobial activity ==


Dermcidin is present in the sweat around 1-10 µg/ml and acts like a regulator of the skin flora in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune response] by inhibiting a large range of bacteria (Gram positive: [https://en.wikipedia.org/wiki/Staphylococcus_aureus_ ''Staphylococcus aureus''], [https://en.wikipedia.org/wiki/Enterococcus_faecalis_ ''Enterococcus faecalis'']; Gram negative: [https://en.wikipedia.org/wiki/Escherichia_coli_ ''Escherichia coli'']) and even fungus ([https://en.wikipedia.org/wiki/Candida_albicans_ ''Candida albicans'']).<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> Its antimicrobial activity is effective under a broad range of pH and high salt concentrations as the human sweat possesses. The sweat is composed of a big percentage of water and electrolytes such as potassium, calcium, magnesium and zinc ions. This is again a principle difference to the other AMPs.<ref name="novel"/>  
Dermcidin is present in the sweat around 1-10 µg/ml and acts like a regulator of the skin flora in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune response] by inhibiting a large range of bacteria (Gram positive: [https://en.wikipedia.org/wiki/Staphylococcus_aureus_ ''Staphylococcus aureus''], [https://en.wikipedia.org/wiki/Enterococcus_faecalis_ ''Enterococcus faecalis'']; Gram negative: [https://en.wikipedia.org/wiki/Escherichia_coli_ ''Escherichia coli'']) and even fungus ([https://en.wikipedia.org/wiki/Candida_albicans_ ''Candida albicans'']).<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> Its antimicrobial activity is effective under a broad range of pH and high salt concentrations as the human sweat possesses. The sweat is composed of99% of water and 1% of electrolytes such as potassium, calcium, magnesium and zinc ions. This is again a principle difference to the other AMPs.<ref name="novel"/>  


The 12 DCD-1L-derived peptides described in the expression and maturation part, play a role in the modulation of the immune response. For example, some of them seems to be more active against ''E. coli'' or ''S.aureus'' than DCD-1L. This is the case of SSL-29, SSL-25 and LEK-24 peptides. Indeed, 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.<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> Therefore 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"/>
The 12 DCD-1L-derived peptides described in the expression and maturation part, play a role in the modulation of the immune response. For example, some of them seems to be more active against ''E. coli'' or ''S.aureus'' than DCD-1L. This is the case of SSL-29, SSL-25 and LEK-24 peptides. Indeed, 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.<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> Therefore 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"/>
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Dermcidin is related to certain cancer diseases such as prostatic cancer<ref> Stewart, G.D., Lowrie, A.G., Riddick, A.C.P., Fearon, K.C.H., Habib, F.K., Ross, J.A., 2007. Dermcidin expression confers a survival advantage in prostate cancer cells subjected to oxidative stress or hypoxia. Prostate 67, 1308–1317. https://doi.org/10.1002/pros.20618</ref>, lung cancer<ref> Chang, W.C., Huang, M.S., Yang, C.J., Wang, W.Y., Lai, T.C., Hsiao, M., Chen, C.H., 2010. Dermcidin identification from exhaled air for lung cancer diagnosis. European Respiratory Journal 35, 1182–1185. https://doi.org/10.1183/09031936.00169509 </ref><ref> López-Sánchez, L.M., Jurado-Gámez, B., Feu-Collado, N., Valverde, A., Cañas, A., Fernández-Rueda, J.L., Aranda, E., Rodríguez-Ariza, A., 2017. Exhaled breath condensate biomarkers for the early diagnosis of lung cancer using proteomics. American Journal of Physiology-Lung Cellular and Molecular Physiology 313, L664–L676. https://doi.org/10.1152/ajplung.00119.2017 </ref>, melanoma<ref> Ortega-Martínez, I., Gardeazabal, J., Erramuzpe, A., Sanchez-Diez, A., Cortés, J., García-Vázquez, M.D., Pérez-Yarza, G., Izu, R., Luís Díaz-Ramón, J., de la Fuente, I.M., Asumendi, A., Boyano, M.D., 2016. Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I-II early-stage melanoma: Vitronectin and dermcidin serum levels in melanoma. Int. J. Cancer 139, 1598–1607. https://doi.org/10.1002/ijc.30202 </ref><ref name="trzoss"> Trzoss, L., Fukuda, T., Costa-Lotufo, L.V., Jimenez, P., La Clair, J.J., Fenical, W., 2014. Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin. Proceedings of the National Academy of Sciences 111, 14687–14692. https://doi.org/10.1073/pnas.1410932111 </ref>, breast cancer<ref> Bancovik, J., Moreira, D.F., Carrasco, D., Yao, J., Porter, D., Moura, R., Camargo, A., Fontes-Oliveira, C.C., Malpartida, M.G., Carambula, S., Vannier, E., Strauss, B.E., Wakamatsu, A., Alves, V.A., Logullo, A.F., Soares, F.A., Polyak, K., Belizário, J.E., 2015. Dermcidin exerts its oncogenic effects in breast cancer via modulation of ERBB signaling. BMC Cancer 15, 70. https://doi.org/10.1186/s12885-015-1022-6 </ref><ref> Brauer, H.A., D’Arcy, M., Libby, T.E., Thompson, H.J., Yasui, Y.Y., Hamajima, N., Li, C.I., Troester, M.A., Lampe, P.D., 2014. Dermcidin expression is associated with disease progression and survival among breast cancer patients. Breast Cancer Res Treat 144, 299–306. https://doi.org/10.1007/s10549-014-2880-3 </ref> and hepatocellular carcinoma.<ref> Ross, J., 2011. Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks. Int J Oncol. https://doi.org/10.3892/ijo.2011.1064 </ref><ref> Shen, S.-L., Qiu, F.-H., Dayarathna, T.K., Wu, J., Kuang, M., Li, S.S.-C., Peng, B.-G., Nie, J., 2011. Identification of Dermcidin as a novel binding protein of Nck1 and characterization of its role in promoting cell migration. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1812, 703–710. https://doi.org/10.1016/j.bbadis.2011.03.004 </ref> Furthermore, it plays a role in lymph node metastasis and gastric cancer.
Dermcidin is related to certain cancer diseases such as prostatic cancer<ref> Stewart, G.D., Lowrie, A.G., Riddick, A.C.P., Fearon, K.C.H., Habib, F.K., Ross, J.A., 2007. Dermcidin expression confers a survival advantage in prostate cancer cells subjected to oxidative stress or hypoxia. Prostate 67, 1308–1317. https://doi.org/10.1002/pros.20618</ref>, lung cancer<ref> Chang, W.C., Huang, M.S., Yang, C.J., Wang, W.Y., Lai, T.C., Hsiao, M., Chen, C.H., 2010. Dermcidin identification from exhaled air for lung cancer diagnosis. European Respiratory Journal 35, 1182–1185. https://doi.org/10.1183/09031936.00169509 </ref><ref> López-Sánchez, L.M., Jurado-Gámez, B., Feu-Collado, N., Valverde, A., Cañas, A., Fernández-Rueda, J.L., Aranda, E., Rodríguez-Ariza, A., 2017. Exhaled breath condensate biomarkers for the early diagnosis of lung cancer using proteomics. American Journal of Physiology-Lung Cellular and Molecular Physiology 313, L664–L676. https://doi.org/10.1152/ajplung.00119.2017 </ref>, melanoma<ref> Ortega-Martínez, I., Gardeazabal, J., Erramuzpe, A., Sanchez-Diez, A., Cortés, J., García-Vázquez, M.D., Pérez-Yarza, G., Izu, R., Luís Díaz-Ramón, J., de la Fuente, I.M., Asumendi, A., Boyano, M.D., 2016. Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I-II early-stage melanoma: Vitronectin and dermcidin serum levels in melanoma. Int. J. Cancer 139, 1598–1607. https://doi.org/10.1002/ijc.30202 </ref><ref name="trzoss"> Trzoss, L., Fukuda, T., Costa-Lotufo, L.V., Jimenez, P., La Clair, J.J., Fenical, W., 2014. Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin. Proceedings of the National Academy of Sciences 111, 14687–14692. https://doi.org/10.1073/pnas.1410932111 </ref>, breast cancer<ref> Bancovik, J., Moreira, D.F., Carrasco, D., Yao, J., Porter, D., Moura, R., Camargo, A., Fontes-Oliveira, C.C., Malpartida, M.G., Carambula, S., Vannier, E., Strauss, B.E., Wakamatsu, A., Alves, V.A., Logullo, A.F., Soares, F.A., Polyak, K., Belizário, J.E., 2015. Dermcidin exerts its oncogenic effects in breast cancer via modulation of ERBB signaling. BMC Cancer 15, 70. https://doi.org/10.1186/s12885-015-1022-6 </ref><ref> Brauer, H.A., D’Arcy, M., Libby, T.E., Thompson, H.J., Yasui, Y.Y., Hamajima, N., Li, C.I., Troester, M.A., Lampe, P.D., 2014. Dermcidin expression is associated with disease progression and survival among breast cancer patients. Breast Cancer Res Treat 144, 299–306. https://doi.org/10.1007/s10549-014-2880-3 </ref> and hepatocellular carcinoma.<ref> Ross, J., 2011. Proteolysis-inducing factor core peptide mediates dermcidin-induced proliferation of hepatic cells through multiple signalling networks. Int J Oncol. https://doi.org/10.3892/ijo.2011.1064 </ref><ref> Shen, S.-L., Qiu, F.-H., Dayarathna, T.K., Wu, J., Kuang, M., Li, S.S.-C., Peng, B.-G., Nie, J., 2011. Identification of Dermcidin as a novel binding protein of Nck1 and characterization of its role in promoting cell migration. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1812, 703–710. https://doi.org/10.1016/j.bbadis.2011.03.004 </ref> Furthermore, it plays a role in lymph node metastasis and gastric cancer.


The gastric cancer cells are characterized by an overexpression of long non coding RNAs ([https://en.wikipedia.org/wiki/Long_non-coding_RNA_ lncRNA]) of stomach cancer associated transcript 3 (shortened as STCAT3). These RNAs, under the RNA form, run some functions of gene regulation such as gene expressions, control of the cell cycle, ect… Dermcidin has been identified as the binding protein of lncRNA STCAT3, but also the dermcidin expression has been shown to be stronger in the case of gastric cancer cells. So in the cancer cells the DCD can be found more abundant than in non-cancer cells. It can be used in the researches on the gastric cancer, hence to save lives in the future.<ref> Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z., 2018. Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. Oncol Rep. https://doi.org/10.3892/or.2018.6673 </ref>
The gastric cancer cells are characterized by an overexpression of long non coding RNAs ([https://en.wikipedia.org/wiki/Long_non-coding_RNA_ lncRNA]) of stomach cancer associated transcript 3 (shortened as STCAT3). These RNAs, under the RNA form, run some functions of gene regulation such as gene expressions, control of the cell cycle, ect… Dermcidin has been identified as the binding protein of lncRNA STCAT3, but also the dermcidin expression has been shown to be stronger in the case of gastric cancer cells. So in the cancer cells the DCD can be found more abundant than in non-cancer cells. This discovery could be used in cancer's research.<ref> Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z., 2018. Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. Oncol Rep. https://doi.org/10.3892/or.2018.6673 </ref>


Often times, dermcidin is in the discussion to function as a general '''biomarker''' for the above mentioned diseases but also being a potential '''target for anticancer drugs''' such as [https://www.biotrend-usa.com/other-products-186/seriniquinone-22200-69-7-566000900.html_ seriniquinone].<ref name="trzoss"/> The anticancer effect could derive from direct interaction or from protein complexes linked via disulfide bonds to DCD, which was already shown for [http://proteopedia.org/wiki/index.php/Hsp70_ Hsp70]. In the survival-promoting peptide area of dermcidin, GNPCH is considered to be an ATP-dependent binding-site for Hsp70.<ref> Stocki, P., Wang, X.N., Morris, N.J., Dickinson, A.M., 2011. HSP70 Natively and Specifically Associates with an N-terminal Dermcidin-derived Peptide That Contains an HLA-A*03 Antigenic Epitope. J. Biol. Chem. 286, 12803–12811. https://doi.org/10.1074/jbc.M110.179630 </ref>
Often times, dermcidin is in the discussion to function as a general '''biomarker''' for the above mentioned diseases but also being a potential '''target for anticancer drugs''' such as [https://www.biotrend-usa.com/other-products-186/seriniquinone-22200-69-7-566000900.html_ seriniquinone].<ref name="trzoss"/> The anticancer effect could derive from direct interaction or from protein complexes linked via disulfide bonds to DCD, which was already shown for [http://proteopedia.org/wiki/index.php/Hsp70_ Hsp70]. In the survival-promoting peptide area of dermcidin, GNPCH is considered to be an ATP-dependent binding-site for Hsp70.<ref> Stocki, P., Wang, X.N., Morris, N.J., Dickinson, A.M., 2011. HSP70 Natively and Specifically Associates with an N-terminal Dermcidin-derived Peptide That Contains an HLA-A*03 Antigenic Epitope. J. Biol. Chem. 286, 12803–12811. https://doi.org/10.1074/jbc.M110.179630 </ref>
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