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'''Dermcidin''' is a '''Human antimicrobial, anionic and ion membrane channel''' ([https://www.rcsb.org/structure/2YMK_ 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 [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ 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 are at their 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:
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] (α-defensins and β-defensins)

Still, some size and structural similarities can be found with the defensin family.<ref name="novel">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</ref>

== Expression and maturation ==

Dermcidin gene (''DCD gene'') is located on the '''chromosome 12''' and constitutively expressed as '''precursor''' of 110 amino acids only in mucous cells of [https://en.wikipedia.org/wiki/Eccrine_sweat_gland_ 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:
''MRFMTLLFLTALAGALVCA''YDPEAASAPGSGNPCHEASAAQKENAGEDPGLARQAPKPRKQR'''SSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSVL''' <ref name="novel"/>

However, some cleavage of the precursor occurres 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.

== Structural highlights ==

<Structure load='2ymk' size='400' frame='true' align='right' caption='Structure of the Dermicidin in the PDB.' />

Dermcidin is an '''anionic channel''' composed of 6 DCD peptides organized in 3 antiparallel peptide dimers and has a dimension of about 8x4 nm.<ref name="girdles">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</ref> 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 <scene name='82/829352/Glu5_glu9_asp42_and_his38/1'> Glu 5, Asp 9, His 38 and Asp 42 </scene> <ref name="girdles"/>. That is why the N-terminal is cationic whereas the C-terminal is anionic.

===Assembly of three monomers===

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 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 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 Zn2+.<ref name="girdles"/>

== Antimicrobial activity ==

Dermcidin is present in the sweat around 1-10 µg/ml. Spread by the sweat over the skin, DCD-1 acts like a regulator of the skin flora. The antimicrobial activity of DCD-1 is not only stable under different pH and salt conditions of the media but also under sweat-similar conditions.<ref> Schittek, B., Hipfel, R., Sauer, B., Bauer, J., Kalbacher, H., Stevanovic, S., Schirle, M., Schroeder, K., Blin, N., Meier, F., Rassner, G., Garbe, C., 2001. Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nat Immunol 2, 1133–1137. https://doi.org/10.1038/ni732 </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 Zn2+.<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>

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"/>

== Related diseases ==

===Skin disorders===

Some skin disorders such as psoriasis are compensate by an overexpression and overproduction of the antimicrobial peptides. The results are that there are less infections on the injured skin.<ref> 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 </ref>

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 <ref name="de"/>.

===Cancer related diseases===

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.

In gastric cancer cell lines which are characterized by an overexpression of [https://en.wikipedia.org/wiki/Long_non-coding_RNA_ lncRNA] of STCAT3, dermcidin represents a binding protein to this RNA. In the cancer tissue the protein can be found more abundant in the cell nucleus and the cytoplasm than in non-cancer tissue. Patients who survived gastric cancer thanks to surgery, show however a decreased level of dermcidin. Further analysis found that the level of dermcidin and STCAT3 expression therefore could be used as clinical predictors for gastric cancer development.<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>

== References ==
<references />