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Dermcidin is a human antimicrobial, anionic ion membrane channel (2YMK) discovered in 2001 based on 6 dermcidin antimicrobial peptides of 110 amino acids present in sweat. Dermcidin expands with other antimicrobial peptides the natural role of the skin to form a barrier to non-human invaders. These peptides, encoded by the DCD gene, play a role in the host defense system as a trimeric channel and thus, are able to prevent infection after injuries or any skin disorders. Scientists are focused on this molecule due to his charge particularity and since antibiotic resistances have been observed.

Homology

The dermcidin peptide sequence has no homology with other known antimicrobial peptide(shortened to AMP). There are two types of AMP, the anionic antimicrobial peptide (AAMP) and the cationic one (CAMP). These two AMP are completing themselves as they reach there activity's optimum under different conditions. Despite AAMP are rare and infrequent in humans, dermcidin is the one of the most analysed AAMP.

Two classes of mammalian and cationic antimicrobial peptides exist:

• Cathelicidins
• Defensins (α-defensins and β-defensins)

Still, some size and structural similarities can be found with the defensin family.^[1]

Expression and maturation

Dermcidin gene (DCD) is located on the chromosome 12 and constitutively expressed as precursor of 110 amino acids only in mucous cells of eccrine sweat glands within the dermis of the skin. The molecular weight of the DCD full-length sequence is 9.3 kDa including the signal peptide (in italic). The peptide is then secreted by granules in sweat and transported to the epidermal surface.

DCD full-length sequence: MRFMTLLFLTALAGALVCAYDPEAASAPGSGNPCHEASAAQKENAGEDPGLARQAPKPRKQRSSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSVL ^[1]

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. 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 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)^[2]. One of them is DCD-1 which lacks the last leucine.

Structural highlights

Dermcidin is an anionic channel composed of 6 DCD peptides organized in 3 antiparallel peptide dimers and has a dimension of about 8x4 nm.^[3] A DCD peptide has a secondary structure of a single α-helix.

Monomer

A monomer is a dimer formed by 2 elongated α-helix tied with 2 zinc ions. These Zn²⁺ ions are linked by N- and C-terminal residues from each α-helix. Residues involved are charged amino acids such as .^[3] That is why the N-terminal is cationic whereas the C-terminal is anionic.

Assembly of three monomers

The trimer is formed by 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. (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  : I,II,III,II,I as they are alternating negative (in blue) and positive (in red) charges.^[3] They create a channel with an overall charge of -12 because DCD-1L peptide is -2.

The amino acids pointing toward the exterior are (in grey) because they are able to interact with the acyl chain of the membrane. They play a role in the cell membrane insertion.^[4]

The bonds between monomers allow the formation of 6 of a diameter of 1 nm (in purple) responsible for ion crossing. The presence of polar residues may have an impact on the selection of ion entry.^[3]

The zinc cofactors

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 Zn²⁺.^[3]

Antimicrobial activity

Dermcidin is present in the sweat around 1-10 µg/ml and acts like a regulator of the skin flora in the innate immune response by inhibiting a large range of bacteria (Gram positive: Staphylococcus aureus, Enterococcus faecalis; Gram negative: Escherichia coli) and even fungus (Candida albicans).^[5] 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 99% of water and 1% of electrolytes such as potassium, calcium, magnesium and zinc ions.

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.^[6] 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.^[2]

More recently studies revealed that DCD-1L creates ion channels into the bacterial membranes promoted by Zn²⁺. ^[5] The complex process of forming such a channel starts with a flat approach to the bacterial membrane. Zn²⁺ 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.^[7] 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.^[4] Finally, computer simulations were able to show that the channel allows aquaporine-like characterstics but with 50-fold higher osmotic water permeability coefficients. This leads to a highly conductive channel that creates a flow of predominant anions across the bacterial membrane. In less than a second, and with only a few channels, the bacterial membrane undergoes a polarity change, killing the bacteria.^[3] Moreover, its anionic nature allows to bypass the defense system of bacteria against AMPs which consists in decreasing the negative charge carried by their plasma membrane so that AMPs - mainly cationic - become less effective. Dermcidin is one of the few anionic AMPs which are not affected by this defense system. ^[8]

Related diseases

Skin disorders

The secretion of antimicrobial peptides on the surface of the skin as well as on other epithelia helps to control the amount of commensal bacteria (for example Staphylococcus epidermidis) or yeast (for example Candida albicans) and to prevent the onset of diseases such as psoriasis. A disturbance in the expression of AMPs leads to recurrent infections in the patient.^[9]

Atopic dermatitis is also linked to DCD peptides. A study proved that patients suffering from this skin disorder have reduced amount of these peptides which could provoke skin infections in contrast to psoriasis.^[5]

Cancer related diseases

Troudht several studies, Dermcidin is often quote as a binding partner related to cancer cells. Among several cancer, prostatic cancer^[10], lung cancer^[11][12], melanoma^[13][14], breast cancer^[15][16] and hepatocellular carcinoma.^[17][18] can be listed.

For instance, in he gastric cancer, cells are characterized by an overexpression of long non coding RNAs (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. In breast cancer dermcidin bind to the protein sGRP78. But also, in some case the dermcidin expression has been shown to be stronger cancer cells. So in the cancer cells the DCD can be found more abundant than in non-cancer cells. This discoveries could be used in cancer's research.^[19]

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 seriniquinone.^[14] The anticancer effect could derive from direct interaction or from protein complexes linked via disulfide bonds to DCD, which was already shown for Hsp70. In the survival-promoting peptide area of dermcidin, GNPCH is considered to be an ATP-dependent binding-site for Hsp70.^[20]

References

1. ↑ ^{1.0 1.1} Birgit Schittek, Rainer Hipfel, Birgit Sauer, Jürgen Bauer, Hubert Kalbacher, Stefan Stevanovic, Markus Schirle, Kristina Schroeder, Nikolaus Blin, Friedegund Meier, Gernot Rassner & Claus Garbe. "Dermcidin: a novel human antibiotic peptide secreted by sweat glands" Nature Immunology 2, no. 12 (December, 2001): 1133-37. https://doi.org/10.1038/ni732
2. ↑ ^{2.0 2.1} 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
3. ↑ ^{3.0 3.1 3.2 3.3 3.4 3.5} Song, C. et al. "Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel." PNAS 110, no. 12 (March 19, 2013): 4586-591. https://doi.org/10.1073/pnas.1214739110
4. ↑ ^{4.0 4.1} 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
5. ↑ ^{5.0 5.1 5.2} 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
6. ↑ 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
7. ↑ 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
8. ↑ Lai Y, Villaruz AE, Li M, Cha DJ, Sturdevant DE, Otto M. The human anionic antimicrobial peptide dermcidin induces proteolytic defence mechanisms in staphylococci. Mol Microbiol. 2007 Jan;63(2):497-506. doi: 10.1111/j.1365-2958.2006.05540.x., Epub 2006 Dec 14. PMID:17176256 doi:http://dx.doi.org/10.1111/j.1365-2958.2006.05540.x
9. ↑ Harder, J., Bartels, J., Christophers, E., Schröder, J.-M., 1997. A peptide antibiotic from human skin. Nature 387, 861–861. https://doi.org/10.1038/43088
10. ↑ 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
11. ↑ 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
12. ↑ 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
13. ↑ 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
14. ↑ ^{14.0 14.1} 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
15. ↑ 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
16. ↑ 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
17. ↑ 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
18. ↑ 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
19. ↑ 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
20. ↑ 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