Proteopedia - User contributions [en]

Sandbox Reserved 1099

2020-01-17T19:09:43Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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 reach there 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 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.

== 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 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 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 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 (comprising Gram positive and Gram negative) and even fungus. Indeed, microbiology tests showed antimicrobial activities 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="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 broad range of pH and high salt concentrations as the human sweat. The sweat is composed of a big percentage of water and electrolytes such as potassium, calcium, magnesium and zinc ions. This is again a key different from the others 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"/>

More recently studies revealed 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> 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.<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"/> Finally, computer simulations were able to show that the channel allows [https://en.wikipedia.org/wiki/Aquaporin_ aquaporine]-like characterstics but with 50-fold higher osmotic water permeability coefficients. This leads to a high-conductive channel which creates a flux of mainly anions across the bacterial membrane. In a time scale of less than one second the pivotal transmembrane potential of bacteria will abrogate caused by only a few channels.<ref name="girdles"/>

== Related diseases ==

===Skin disorders===

Some skin disorders such as psoriasis are compensate by an overexpression and overproduction of the antimicrobial peptides. As a result infections on the injured skin are less frequent.<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.

The gastric cancer is 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 genes regulation such as gene expressions, control of the cell cycle, ect… Not only Dermicidin has been identified as the binding protein of lncRNA STCAT3, but also the Dermicidin expression has been shown 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.<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 />

Sandbox Reserved 1099

2020-01-17T17:58:53Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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 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 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 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 (comprising Gram positive and Gram negative) and even fungus. Indeed, microbiology tests showed antimicrobial activities 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="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 broad range of pH and high salt concentrations as the human sweat. The sweat is composed in fact of a big percentage of water and electrolytes such as potassium, calcium, magnesium and zinc ions. This is again a key point different from the others 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. 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>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"/>

However, more recently studies revealed new information<ref name="girdles"/>, namely, it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn2+ <ref name="de">. That is the currently accepted opinion. The complex process of forming such a channel starts with a flat approach (DCD peptides) to the bacterial membrane. Zn2+ stabilizes the slow formation of oligomeric complexes (monomer) 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"/> Finally, computer simulations were able to show that the channel allows [https://en.wikipedia.org/wiki/Aquaporin_ aquaporine]-like characterstics but with 50-fold higher osmotic water permeability coefficients. This leads to a high-conductive channel which creates a flux of mainly anions across the bacterial membrane. In a time scale of less than one second the pivotal transmembrane potential of bacteria will abrogate caused by only a few channels.<ref name="girdles"/>

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, more recently studies revealed new information<ref name="girdles"/>, in fact, 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> 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.<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"/> 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 high-conductive channel which creates a flux of mainly anions across the bacterial membrane. In a time scale of less than one second the pivotal transmembrane potential of bacteria will abrogate caused by only a few channels.<ref name="girdles"/>

== 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.

The gastric cancer is 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 genes regulation such as gene expressions, control of the cell cycle, ect… Not only Dermicidin has been identified as the binding protein of lncRNA STCAT3, but also the Dermicidin expression has been shown 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.<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 />

Sandbox Reserved 1099

2020-01-17T12:54:59Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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 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 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.

The gastric cancer is 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 genes regulation such as gene expressions, control of the cell cycle, ect… Not only Dermicidin has been identified as the binding protein of lncRNA STCAT3, but also the Dermicidin expression has been shown 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.<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 />

Sandbox Reserved 1099

2020-01-17T11:57:39Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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.<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.

== 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). And 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> 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>

DCD-1L is further processed ''in vitro'' but also in human sweat by the aspartate protease [https://www.uniprot.org/uniprot/P07339_ cathepsin D] (CatD) which cleaves between L44 and D45 and almost completely between L29 and E30. Actually, even more DCD-1L-derived peptides, namely 12, 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 ==

===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>

===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>

== References ==
<references />

Sandbox Reserved 1099

2020-01-16T22:52:36Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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. The skin's role is to be a barrier, and it is thanks to all the antimicrobial peptides such as Dermicidin that it can be fulfill. 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) or the cationic one (CAMP). These two AMP are completing themselves as they are at their best activities in different conditions. Despite AAMP are rare and infrequent in Human, the dermicidin 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)

But, 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 occurred probably in sweat to produce different active forms of dermcidin peptide. The most abundant proteolytically processed DCD peptide presents in sweat is '''DCD-1L''' (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 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.<ref>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.

== 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 so hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be localized in the bond area too neglecting positive amino acids. In total, 96 residues are ionizable and 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 alterning negative (in blue) and positive (in red) charge <ref name="girdles"/>. They create a channel 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). And the presence of polar residues may have an impact on the selection of ion entry <ref name="girdles"/>.

===The zinc cofactors===

The zinc ions are found in sweat particularly enriched in divalent ions. Their presence is fundamental as if there are not here, dermcidin is no longer a channel. And the high permeability for water and conductance of the channel is allowed by Zn2+.<ref name="girdles"/>

== Antimicrobial activity ==

In mammalian skin two classes of peptides with antibacterial function are present such as cathelicidins<ref> Gallo, R.L., Ono, M., Povsic, T., Page, C., Eriksson, E., Klagsbrun, M., Bernfield, M., 1994. Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proceedings of the National Academy of Sciences 91, 11035–11039. https://doi.org/10.1073/pnas.91.23.11035 </ref> and β-defensins.<ref name="harder"> 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> Dermcidin forms another category of antimicrobial peptides expressed in human eccrine sweat glands. The dark mucous cells of the sweat glands produce DCD which is then found in the golgi complex and in secretory granules. After proteolytic processes, a form of 47 amino acids (DCD-1) of the original C-terminus 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> 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>

== Related diseases ==

===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>

===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 name="harder"/>

== References ==
<references />

Sandbox Reserved 1099

2020-01-16T20:37:01Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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. The skin's role is to be a barrier, and it is thanks to all the antimicrobial peptides such as Dermicidin that it can be fulfill. 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) or the cationic one (CAMP). These two AMP are completing themselves as they are at their best activities in different conditions. Despite AAMP are rare and infrequent in Human, the dermicidin 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)

But, 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 clivage of the precursor occurred probably in sweat to produce different active forms of dermcidin peptide. The most abundant proteolytically processed DCD peptide presents in sweat is '''DCD-1L''' (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 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 <ref>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.

== 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 and 9, His 38 and Asp 42 </scene> <ref name="girdles"/>. That is why, 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 so hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be localized in the bond area too neglecting positive amino acids. In total, 96 residues are ionizable and 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 alterning negative (in blue) and positive (in red) charge <ref name="girdles"/>. They create a channel 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). And the presence of polar residues may have an impact on the selection of ion entry <ref name="girdles"/>.

===The zinc cofactors===

The zinc ions are found in sweat particularly enriched in divalent ions. Their presence is fundamental as if there are not here, dermcidin is no longer a channel. And the high permeability for water and conductance of the channel is allowed by Zn2+ <ref name="girdles"/>.

== Antimicrobial activity ==

In mammalian skin two classes of peptides with antibacterial function are present such as cathelicidins<ref> Gallo, R.L., Ono, M., Povsic, T., Page, C., Eriksson, E., Klagsbrun, M., Bernfield, M., 1994. Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proceedings of the National Academy of Sciences 91, 11035–11039. https://doi.org/10.1073/pnas.91.23.11035 </ref> and β-defensins.<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> Dermcidin forms another category of antimicrobial peptides expressed in human eccrine sweat glands. The dark mucous cells of the sweat glands produce DCD which is then found in the golgi complex and in secretory granules. After proteolytic processes, a form of 47 amino acids (DCD-1) of the original C-terminus 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> 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 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> Song, C., Weichbrodt, C., Salnikov, E.S., Dynowski, M., Forsberg, B.O., Bechinger, B., Steinem, C., de Groot, B.L., Zachariae, U., Zeth, K., 2013. Crystal structure and functional mechanism of a human antimicrobial membrane channel. Proceedings of the National Academy of Sciences 110, 4586–4591. https://doi.org/10.1073/pnas.1214739110 </ref> since it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn2+.<ref> 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>

derived peptides described before modulate immune response (against particular micro-organism)

== Related diseases ==

===Cancer related illnesses===

So far, it is published that 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> 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> 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> 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]. 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>

===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

== References ==
<references />

Sandbox Reserved 1099

2020-01-16T20:17:46Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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. The skin's role is to be a barrier, and it is thanks to all the antimicrobial peptides such as Dermicidin that it can be fulfill. 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) or the cationic one (CAMP). These two AMP are completing themselves as they are at their best activities in different conditions. Despite AAMP are rare and infrequent in Human, the dermicidin 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)

But, 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 clivage of the precursor occurred probably in sweat to produce different active forms of dermcidin peptide. The most abundant proteolytically processed DCD peptide presents in sweat is '''DCD-1L''' (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 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 <ref>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.

== 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 and 9, His 38 and Asp 42 </scene> <ref name="girdles"/>. That is why, 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 so hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be localized in the bond area too neglecting positive amino acids. In total, 96 residues are ionizable and 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 alterning negative (in blue) and positive (in red) charge <ref name="girdles"/>. They create a channel 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). And the presence of polar residues may have an impact on the selection of ion entry <ref name="girdles"/>.

===The zinc cofactors===

The zinc ions are found in sweat particularly enriched in divalent ions. Their presence is fundamental as if there are not here, dermcidin is no longer a channel. And the high permeability for water and conductance of the channel is allowed by Zn2+ <ref name="girdles"/>.

== Antimicrobial activity ==

In mammalian skin two classes of peptides with antibacterial function are present such as cathelicidins<ref> Gallo, R.L., Ono, M., Povsic, T., Page, C., Eriksson, E., Klagsbrun, M., Bernfield, M., 1994. Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proceedings of the National Academy of Sciences 91, 11035–11039. https://doi.org/10.1073/pnas.91.23.11035 </ref> and β-defensins.<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> Dermcidin forms another category of antimicrobial peptides expressed in human eccrine sweat glands. The dark mucous cells of the sweat glands produce DCD which is then found in the golgi complex and in secretory granules. After proteolytic processes, a form of 47 amino acids (DCD-1) of the original C-terminus 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> 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 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> Song, C., Weichbrodt, C., Salnikov, E.S., Dynowski, M., Forsberg, B.O., Bechinger, B., Steinem, C., de Groot, B.L., Zachariae, U., Zeth, K., 2013. Crystal structure and functional mechanism of a human antimicrobial membrane channel. Proceedings of the National Academy of Sciences 110, 4586–4591. https://doi.org/10.1073/pnas.1214739110 </ref> since it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn2+.<ref> 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>

derived peptides described before modulate immune response (against particular micro-organism)

== Related disease ==

So far, it is published that 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> 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 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 therefor 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 serinquinone.<ref> 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> The anticancer effect could derive from direct interaction or from protein complexes linked via disulfide bonds to DCD, which was already shown 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 />

Sandbox Reserved 1099

2020-01-16T20:16:58Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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. The skin's role is to be a barrier, and it is thanks to all the antimicrobial peptide as Dermicidin that it can be fulfill. 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) or the cationic one (CAMP). These two AMP are completing themselves as they are at their best activities in different conditions. Despite AAMP are rare and infrequent in Human, the dermicidin 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)

But, 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 clivage of the precursor occurred probably in sweat to produce different active forms of dermcidin peptide. The most abundant proteolytically processed DCD peptide presents in sweat is '''DCD-1L''' (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 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 <ref>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.

== 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 and 9, His 38 and Asp 42 </scene> <ref name="girdles"/>. That is why, 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 so hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be localized in the bond area too neglecting positive amino acids. In total, 96 residues are ionizable and 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 alterning negative (in blue) and positive (in red) charge <ref name="girdles"/>. They create a channel 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). And the presence of polar residues may have an impact on the selection of ion entry <ref name="girdles"/>.

===The zinc cofactors===

The zinc ions are found in sweat particularly enriched in divalent ions. Their presence is fundamental as if there are not here, dermcidin is no longer a channel. And the high permeability for water and conductance of the channel is allowed by Zn2+ <ref name="girdles"/>.

== Antimicrobial activity ==

In mammalian skin two classes of peptides with antibacterial function are present such as cathelicidins<ref> Gallo, R.L., Ono, M., Povsic, T., Page, C., Eriksson, E., Klagsbrun, M., Bernfield, M., 1994. Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proceedings of the National Academy of Sciences 91, 11035–11039. https://doi.org/10.1073/pnas.91.23.11035 </ref> and β-defensins.<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> Dermcidin forms another category of antimicrobial peptides expressed in human eccrine sweat glands. The dark mucous cells of the sweat glands produce DCD which is then found in the golgi complex and in secretory granules. After proteolytic processes, a form of 47 amino acids (DCD-1) of the original C-terminus 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> 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 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> Song, C., Weichbrodt, C., Salnikov, E.S., Dynowski, M., Forsberg, B.O., Bechinger, B., Steinem, C., de Groot, B.L., Zachariae, U., Zeth, K., 2013. Crystal structure and functional mechanism of a human antimicrobial membrane channel. Proceedings of the National Academy of Sciences 110, 4586–4591. https://doi.org/10.1073/pnas.1214739110 </ref> since it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn2+.<ref> 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>

derived peptides described before modulate immune response (against particular micro-organism)

== Related disease ==

So far, it is published that 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> 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 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 therefor 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 serinquinone.<ref> 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> The anticancer effect could derive from direct interaction or from protein complexes linked via disulfide bonds to DCD, which was already shown 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 />

Sandbox Reserved 1099

2020-01-16T20:16:05Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''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. 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. ''The skin's role is to be a barrier, and it is thanks to all the antimicrobial peptide as Dermicidin that it can be fulfill.''

==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) or the cationic one (CAMP). These two AMP are completing themselves as they are at their best activities in different conditions. Despite AAMP are rare and infrequent in Human, the dermicidin 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)

But, 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 clivage of the precursor occurred probably in sweat to produce different active forms of dermcidin peptide. The most abundant proteolytically processed DCD peptide presents in sweat is '''DCD-1L''' (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 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 <ref>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.

== 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 and 9, His 38 and Asp 42 </scene> <ref name="girdles"/>. That is why, 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 so hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be localized in the bond area too neglecting positive amino acids. In total, 96 residues are ionizable and 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 alterning negative (in blue) and positive (in red) charge <ref name="girdles"/>. They create a channel 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). And the presence of polar residues may have an impact on the selection of ion entry <ref name="girdles"/>.

===The zinc cofactors===

The zinc ions are found in sweat particularly enriched in divalent ions. Their presence is fundamental as if there are not here, dermcidin is no longer a channel. And the high permeability for water and conductance of the channel is allowed by Zn2+ <ref name="girdles"/>.

== Antimicrobial activity ==

In mammalian skin two classes of peptides with antibacterial function are present such as cathelicidins<ref> Gallo, R.L., Ono, M., Povsic, T., Page, C., Eriksson, E., Klagsbrun, M., Bernfield, M., 1994. Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proceedings of the National Academy of Sciences 91, 11035–11039. https://doi.org/10.1073/pnas.91.23.11035 </ref> and β-defensins.<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> Dermcidin forms another category of antimicrobial peptides expressed in human eccrine sweat glands. The dark mucous cells of the sweat glands produce DCD which is then found in the golgi complex and in secretory granules. After proteolytic processes, a form of 47 amino acids (DCD-1) of the original C-terminus 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> 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 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> Song, C., Weichbrodt, C., Salnikov, E.S., Dynowski, M., Forsberg, B.O., Bechinger, B., Steinem, C., de Groot, B.L., Zachariae, U., Zeth, K., 2013. Crystal structure and functional mechanism of a human antimicrobial membrane channel. Proceedings of the National Academy of Sciences 110, 4586–4591. https://doi.org/10.1073/pnas.1214739110 </ref> since it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn2+.<ref> 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>

derived peptides described before modulate immune response (against particular micro-organism)

== Related disease ==

So far, it is published that 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> 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 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 therefor 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 serinquinone.<ref> 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> The anticancer effect could derive from direct interaction or from protein complexes linked via disulfide bonds to DCD, which was already shown 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 />

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Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

'''Dermcidin''' is a '''Human''' [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ antimicrobial peptide] (shortened to AMP) of 110 amino acids presents in sweat. This molecule encoded by the ''DCD gene'' plays a role in the host defense system as a trimeric channel and thus, is able to prevent infection after injuries or any skin disorders. There are two types of AMP, the anionic antimicobial peptide (AAMP) or the cationic one (CAMP). These two AMP are completing themselves as they are at their best activities in different conditions. Despite AAMP are rare and infrequent in Human, the Dermicidin is the one of the most analysed AAMP.

== Expression ==

Dermcidin gene 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 derived-peptide is then secreted by granules in sweat.

The Dermcidin peptide sequence has no homology with other known antimicrobial peptides. Two classes of mammalian antimicrobial peptides exist :
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] which are cationic peptides (α-defensins and β-defensins)

But, some size and structural similarities can be found with the defensin family. <ref>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://www.nature.com/articles/ni732</ref>

The molecular weight of the DCD full-length sequence is 9,3 kDa including the signal peptide. In that way, many DCD forms could be proteolytically processed. But the most abundant DCD peptide presents in sweat is '''DCD-1L'''.

DCD-1L contains the C-terminal end from the 63 to the 110 residue. This peptide is probably created by combination of proteases in sweat. The cathepsin D, 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease are involved in the post-secretory processing of DCD-1L <ref>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. http://www.jbc.org/content/281/9/5406.long </ref>.

== 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 or 3 antiparallel peptide, structured as α-helix, dimers, and has a dimension of about 8x4 nm. <ref>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://www.pnas.org/content/110/12/4586</ref>

* Monomer :

A monomer is 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 and 9, His 38 and Asp 42 </scene>. That is why, 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 so hydrophilic residues. <scene name='82/829352/Hydrophobic_polar/1'>Polar</scene> (in pink) amino acids can be localized in the bond area too neglecting positive amino acids. In total, 96 residues are ionizable and 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 alterning negative (in blue) and positive (in red) charge. <ref>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://www.pnas.org/content/110/12/4586</ref>. They create a channel 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. And the presence of polar residues may have an impact on the selection of ion entry.

*The zinc cofactors :

The zinc ions are fundamental as if there are not here, Dermcidin is no longer a channel. And the high permeability and conductance of the channel is allowed by Zn2+.

== Antimicrobial activity ==

They may be effective because the sweat is acidic and composed of salt concentration such as sodium, chloride, potassium and magnesium.This form is involved in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune system] and protect from a variety of pathogenic microorganisms. N-ter interact with negatively charges from phospholipid of bacteria membrane ??

== Related disease ==

atomic dermatitis ...

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references />
1. Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013
2. Maren Paulmann, Thomas Arnold, Dirk Linke, Suat Özdirekcan, Annika Kopp, Thomas Gutsmann, Hubert Kalbacher, Ines Wanke, Verena J. Schuenemann, Michael Habeck, Jochen Bürck, Anne S. Ulrich and Birgit Schittek :Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat
3. 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
4. H. Steffen, S. Rieg, I. Wiedemann, H. Kalbacher, M. Deeg, H.-G. Sahl, A. Peschel, F. Götz, C. Garbe, B. Schittek : Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge.
5. Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z. : Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. 2018

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Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

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

'''Dermcidin''' is a '''Human''' [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ antimicrobial peptide] of 110 amino acids presents in sweat. This molecule encoded by the ''DCD gene'' plays a role in the host defense system as a trimeric channel and thus, is able to prevent infection after injuries or any skin disorders.

== Expression ==

Dermcidin gene is located on the '''chromosome 12''' and constitutively expressed as '''precursor''' only in mucous cells of eccrine sweat glands within the dermis of the skin. The derived-peptide is then secreted by granules in sweat.

The Dermcidin peptide sequence has no homology with other known antimicrobial peptides. Two classes of mammalian antimicrobial peptides exist :
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] which are cationic peptides (α-defensins and β-defensins)

But, some size and structural similarities can be found with the defensin family. <ref>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://www.nature.com/articles/ni732</ref>

The molecular weight of the DCD full-length sequence (110 amino acids) is 9,3 kDa including the signal peptide. In that way, many DCD forms could be proteolytically processed. But the most abundant DCD peptide presents in sweat is '''DCD-1L'''.

DCD-1L contains the C-terminal end from the 63 to the 110 residue. This peptide is probably created by combination of proteases in sweat. The cathepsin D, 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease are involved in the post-secretory processing of DCD-1L <ref>[[ J. Biol. Chem.-2006-Baechle-5406-15]], </ref>.

== Structural highlights ==

Dermcidin is an '''anionic channel''' composed of 6 DCD peptides or 3 antiparallel peptide dimers, and has a dimension of about 8x4 nm. <ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

* Monomer :

A monomer is 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 and 9, His 38 and Asp 42 </scene>. That is why, 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 and positively charged residues so hydrophilic residues. Polar amino acids can be localized in the bond area too. In total, 96 residues are ionizable and which are all facing toward the interior of the tunnel. They are creating a channel overall charge of -12 because DCD-1L peptide is -2. However, the amino acids pointing toward the exterior are hydrophobic because they are able to interact with the acyl chain of the membrane. They play a role in the cell membrane insertion.
The conformation of the charged residues formed <scene name='82/829352/Girdles/1'>five girdles</scene> as I,II,III,II,I ; as they are alterning negative (in blue) and positive (in red) global charge.<ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

The bonds between monomers allow the formation of 6 lateral openings of a diameter of 1 nm. And the presence of small (such as polar amino acids) and positive residues may have an impact on the selection of ion entry.

*The zinc cofactors :

The zinc ions are fundamental as if there are not here, Dermcidin is no longer a channel. And the high permeability and conductance of the channel is allowed by Zn2+.

== Antimicrobial activity ==

They may be effective because the sweat is acidic and composed of salt concentration such as sodium, chloride, potassium and magnesium.This form is involved in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune system] and protect from a variety of pathogenic microorganisms. N-ter interact with negatively charges from phospholipid of bacteria membrane ??

== Related disease ==

atomic dermatitis ...

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references />
1. Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013
2. Maren Paulmann, Thomas Arnold, Dirk Linke, Suat Özdirekcan, Annika Kopp, Thomas Gutsmann, Hubert Kalbacher, Ines Wanke, Verena J. Schuenemann, Michael Habeck, Jochen Bürck, Anne S. Ulrich and Birgit Schittek :Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat
3. 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
4. H. Steffen, S. Rieg, I. Wiedemann, H. Kalbacher, M. Deeg, H.-G. Sahl, A. Peschel, F. Götz, C. Garbe, B. Schittek : Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge.
5. Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z. : Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. 2018

Sandbox Reserved 1099

2020-01-13T21:46:48Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

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

'''Dermcidin''' is a '''Human''' [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ antimicrobial peptide] of 110 amino acids presents in sweat. This molecule encoded by the ''DCD gene'' plays a role in the host defense system as a trimeric channel and thus, is able to prevent infection after injuries or any skin disorders.

== Expression ==

Dermcidin gene is located on the '''chromosome 12''' and constitutively expressed as '''precursor''' only in mucous cells of eccrine sweat glands within the dermis of the skin. The derived-peptide is then secreted by granules in sweat. <ref>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</ref>

The Dermcidin peptide sequence has no homology with other known antimicrobial peptides. Two classes of mammalian antimicrobial peptides exist :
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] which are cationic peptides (α-defensins and β-defensins)

But, some size and structural similarities can be found with the defensin family.

The molecular weight of the DCD full-length sequence (110 amino acids) is 9,3 kDa including the signal peptide. In that way, many DCD forms could be proteolytically processed. But the most abundant DCD peptide presents in sweat is '''DCD-1L'''.

DCD-1L contains the C-terminal end from the 63 to the 110 residue. This peptide is probably created by combination of proteases in sweat. The cathepsin D, 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease are involved in the post-secretory processing of DCD-1L <ref>[[ J. Biol. Chem.-2006-Baechle-5406-15]], </ref>.

== Structural highlights ==

Dermcidin is an '''anionic channel''' composed of 6 DCD peptides or 3 antiparallel peptide dimers, and has a dimension of about 8x4 nm. <ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

* Monomer :

A monomer is 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 and 9, His 38 and Asp 42 </scene>. That is why, 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 and positively charged residues so hydrophilic residues. Polar amino acids can be localized in the bond area too. In total, 96 residues are ionizable and which are all facing toward the interior of the tunnel. They are creating a channel overall charge of -12 because DCD-1L peptide is -2. However, the amino acids pointing toward the exterior are hydrophobic because they are able to interact with the acyl chain of the membrane. They play a role in the cell membrane insertion. The conformation of the charged residues formed <scene name='82/829352/Girdles/1'>five girdles</scene> as I,II,III,II,I ; as they are alterning negative (in blue) and positive (in red) global charge.<ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

The bonds between monomers allow the formation of 6 lateral openings of a diameter of 1 nm. And the presence of small (such as polar amino acids) and positive residues may have an impact on the selection of ion entry.

*The zinc cofactors :

The zinc ions are fundamental as if there are not here, Dermcidin is no longer a channel. And the high permeability and conductance of the channel is allowed by Zn2+.

== Antimicrobial activity ==

They may be effective because the sweat is acidic and composed of salt concentration such as sodium, chloride, potassium and magnesium.This form is involved in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune system] and protect from a variety of pathogenic microorganisms. N-ter interact with negatively charges from phospholipid of bacteria membrane ??

== Related disease ==

atomic dermatitis ...

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references />
1. Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013
2. Maren Paulmann, Thomas Arnold, Dirk Linke, Suat Özdirekcan, Annika Kopp, Thomas Gutsmann, Hubert Kalbacher, Ines Wanke, Verena J. Schuenemann, Michael Habeck, Jochen Bürck, Anne S. Ulrich and Birgit Schittek :Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat
3. 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
4. H. Steffen, S. Rieg, I. Wiedemann, H. Kalbacher, M. Deeg, H.-G. Sahl, A. Peschel, F. Götz, C. Garbe, B. Schittek : Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge.
5. Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z. : Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. 2018

Sandbox Reserved 1099

2020-01-13T21:20:51Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

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

'''Dermcidin''' is a '''Human''' [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ antimicrobial peptide] of 110 amino acids presents in sweat. This molecule encoded by the ''DCD gene'' plays a role in the host defense system as a trimeric channel and thus, is able to prevent infection after injuries or any skin disorders.

== Expression ==

Dermcidin gene is located on the '''chromosome 12''' and constitutively expressed as '''precursor''' only in mucous cells of eccrine sweat glands within the dermis of the skin. The derived-peptide is then secreted by granules in sweat. <ref>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</ref>

The Dermcidin peptide sequence has no homology with other known antimicrobial peptides. Two classes of mammalian antimicrobial peptides exist :
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] which are cationic peptides (α-defensins and β-defensins)

But, some size and structural similarities can be found with the defensin family.

The molecular weight of the DCD full-length sequence (110 amino acids) is 9,3 kDa including the signal peptide. In that way, many DCD forms could be proteolytically processed. But the most abundant DCD peptide presents in sweat is '''DCD-1L'''.

DCD-1L contains the C-terminal end from the 63 to the 110 residue. This peptide is probably created by combination of proteases in sweat. The cathepsin D, 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease are involved in the post-secretory processing of DCD-1L <ref>[[ J. Biol. Chem.-2006-Baechle-5406-15]], </ref>.

== Structural highlights ==

Dermcidin is an '''anionic channel''' composed of 6 DCD peptides or 3 antiparallel peptide dimers, and has a dimension of about 8x4 nm. <ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

* Monomer :

A monomer is 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 Glu 5 and 9, Asp 42 and His 38. That is why, 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 and positively charged residues so hydrophilic residues. Polar amino acids can be localized in the bond area too. In total, 96 residues are ionizable and which are all facing toward the interior of the tunnel. They are creating a channel overall charge of -12 because DCD-1L peptide is -2. However, the amino acids pointing toward the exterior are hydrophobic because they are able to interact with the acyl chain of the membrane. The conformation of the charged residues formed <scene name='82/829352/Girdles/1'>five girdles</scene> as I,II,III,II,I ; as they are alterning negative (in blue) and positive (in red) global charge.<ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>They play a role in the cell membrane insertion.

The bonds between monomers allow the formation of 6 lateral openings of a diameter of 1 nm. And the presence of small (such as polar amino acids) and positive residues may have an impact on the selection of ion entry.

*The zinc cofactors :

The zinc ions are fundamental as if there are not here, Dermcidin is no longer a channel. And the high permeability and conductance of the channel is allowed by Zn2+.

== Antimicrobial activity ==

They may be effective because the sweat is acidic and composed of salt concentration such as sodium, chloride, potassium and magnesium.This form is involved in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune system] and protect from a variety of pathogenic microorganisms. N-ter interact with negatively charges from phospholipid of bacteria membrane ??

== Related disease ==

atomic dermatitis ...

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references />
1. Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013
2. Maren Paulmann, Thomas Arnold, Dirk Linke, Suat Özdirekcan, Annika Kopp, Thomas Gutsmann, Hubert Kalbacher, Ines Wanke, Verena J. Schuenemann, Michael Habeck, Jochen Bürck, Anne S. Ulrich and Birgit Schittek :Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat
3. 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
4. H. Steffen, S. Rieg, I. Wiedemann, H. Kalbacher, M. Deeg, H.-G. Sahl, A. Peschel, F. Götz, C. Garbe, B. Schittek : Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge.
5. Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z. : Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. 2018

Sandbox Reserved 1099

2020-01-13T21:06:28Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

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

'''Dermcidin''' is a '''Human''' [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ antimicrobial peptide] of 110 amino acids presents in sweat. This molecule encoded by the ''DCD gene'' plays a role in the host defense system as a trimeric channel and thus, is able to prevent infection after injuries or any skin disorders.

== Expression ==

Dermcidin gene is located on the '''chromosome 12''' and constitutively expressed as '''precursor''' only in mucous cells of eccrine sweat glands within the dermis of the skin. The derived-peptide is then secreted by granules in sweat. <ref>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</ref>

The Dermcidin peptide sequence has no homology with other known antimicrobial peptides. Two classes of mammalian antimicrobial peptides exist :
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] which are cationic peptides (α-defensins and β-defensins)

But, some size and structural similarities can be found with the defensin family.

The molecular weight of the DCD full-length sequence (110 amino acids) is 9,3 kDa including the signal peptide. In that way, many DCD forms could be proteolytically processed. But the most abundant DCD peptide presents in sweat is '''DCD-1L'''.

DCD-1L contains the C-terminal end from the 63 to the 110 residue. This peptide is probably created by combination of proteases in sweat. The cathepsin D, 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease are involved in the post-secretory processing of DCD-1L <ref>[[ J. Biol. Chem.-2006-Baechle-5406-15]], </ref>.

== Structural highlights ==

Dermcidin is an '''anionic channel''' composed of 6 DCD peptides or 3 antiparallel peptide dimers, and has a dimension of about 8x4 nm. <ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

* Monomer :

A monomer is 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 Glu 5 and 9, Asp 42 and His 38. That is why, 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 and positively charged residues so hydrophilic residues. Polar amino acids can be localized in the bond area too. In total, 96 residues are ionizable and which are all facing toward the interior of the tunnel. They are creating a channel overall charge of -12 because DCD-1L peptide is -2. However, the amino acids pointing toward the exterior are hydrophobic because they are able to interact with the acyl chain of the membrane. They play a role in the cell membrane insertion. The DCD can be cut in <scene name='82/829352/Girdles/1'>five girdles</scene> as I,II,III,II,I alterning negative (in blue) and positive (in red) global charge.<ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

The bonds between monomers allow the formation of 6 lateral openings of a diameter of 1 nm. And the presence of small (such as polar amino acids) and positive residues may have an impact on the selection of ion entry.

*The zinc cofactors :

The zinc ions are fundamental as if there are not here, Dermcidin is no longer a channel. And the high permeability and conductance of the channel is allowed by Zn2+.

== Antimicrobial activity ==

They may be effective because the sweat is acidic and composed of salt concentration such as sodium, chloride, potassium and magnesium.This form is involved in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune system] and protect from a variety of pathogenic microorganisms. N-ter interact with negatively charges from phospholipid of bacteria membrane ??

== Related disease ==

atomic dermatitis ...

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references />
1. Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013
2. Maren Paulmann, Thomas Arnold, Dirk Linke, Suat Özdirekcan, Annika Kopp, Thomas Gutsmann, Hubert Kalbacher, Ines Wanke, Verena J. Schuenemann, Michael Habeck, Jochen Bürck, Anne S. Ulrich and Birgit Schittek :Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat
3. 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
4. H. Steffen, S. Rieg, I. Wiedemann, H. Kalbacher, M. Deeg, H.-G. Sahl, A. Peschel, F. Götz, C. Garbe, B. Schittek : Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge.
5. Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z. : Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. 2018

Sandbox Reserved 1099

2020-01-13T20:31:39Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

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

'''Dermcidin''' is a '''Human''' [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ antimicrobial peptide] of 110 amino acids presents in sweat. This molecule encoded by the ''DCD gene'' plays a role in the host defense system as a trimeric channel and thus, is able to prevent infection after injuries or any skin disorders.

== Expression ==

Dermcidin gene is located on the '''chromosome 12''' and constitutively expressed as '''precursor''' only in mucous cells of eccrine sweat glands within the dermis of the skin. The derived-peptide is then secreted by granules in sweat. <ref>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</ref>

The Dermcidin peptide sequence has no homology with other known antimicrobial peptides. Two classes of mammalian antimicrobial peptides exist :
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] which are cationic peptides (α-defensins and β-defensins)

But, some size and structural similarities can be found with the defensin family.

The molecular weight of the DCD full-length sequence (110 amino acids) is 9,3 kDa including the signal peptide. In that way, many DCD forms could be proteolytically processed. But the most abundant DCD peptide presents in sweat is '''DCD-1L'''.

DCD-1L contains the C-terminal end from the 63 to the 110 residue. This peptide is probably created by combination of proteases in sweat. The cathepsin D, 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease are involved in the post-secretory processing of DCD-1L <ref>[[ J. Biol. Chem.-2006-Baechle-5406-15]], </ref>.

== Structural highlights ==

Dermcidin is an '''anionic channel''' composed of 6 DCD peptides or 3 antiparallel peptide dimers, and has a dimension of about 8x4 nm. <ref>Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013 [[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607029/#!po=50.0000]]</ref>

* Monomer :

A monomer is 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 Glu 5 and 9, Asp 42 and His 38. That is why, 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 and positively charged residues so hydrophilic residues. Polar amino acids can be localized in the bond area too. In total, 96 residues are ionizable and which are all facing toward the interior of the tunnel. They are creating a channel overall charge of -12 because DCD-1L peptide is -2. However, the amino acids pointing toward the exterior are hydrophobic because they are able to interact with the acyl chain of the membrane. They play a role in the cell membrane insertion.

The bonds between monomers allow the formation of 6 lateral openings of a diameter of 1 nm. And the presence of small (such as polar amino acids) and positive residues may have an impact on the selection of ion entry.

*The zinc cofactors :

The zinc ions are fundamental as if there are not here, Dermcidin is no longer a channel. And the high permeability and conductance of the channel is allowed by Zn2+.

== Antimicrobial activity ==

They may be effective because the sweat is acidic and composed of salt concentration such as sodium, chloride, potassium and magnesium.This form is involved in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune system] and protect from a variety of pathogenic microorganisms. N-ter interact with negatively charges from phospholipid of bacteria membrane ??

== Related disease ==

atomic dermatitis ...

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references />
1. Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013
2. Maren Paulmann, Thomas Arnold, Dirk Linke, Suat Özdirekcan, Annika Kopp, Thomas Gutsmann, Hubert Kalbacher, Ines Wanke, Verena J. Schuenemann, Michael Habeck, Jochen Bürck, Anne S. Ulrich and Birgit Schittek :Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat
3. 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
4. H. Steffen, S. Rieg, I. Wiedemann, H. Kalbacher, M. Deeg, H.-G. Sahl, A. Peschel, F. Götz, C. Garbe, B. Schittek : Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge.
5. Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z. : Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. 2018

Sandbox Reserved 1099

2020-01-12T19:45:02Z

Laetitia Vandoorn:

{{Sandbox_ESBS_2019}}

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

'''Dermcidin''' is a '''Human''' [https://en.wikipedia.org/wiki/Antimicrobial_peptides_ antimicrobial peptide] of 110 amino acids presents in sweat involved in the regulation of skin flora. This molecule encoded by the ''DCD gene'' plays a role in the host defense system as a trimeric channel and thus, is able to prevent infection after injuries or any skin disorders.

== Expression and function ==

Dermcidin gene is located on the chromosome 12 and expressed as precursor only in mucous cells of eccrine sweat glands within the dermis of the skin and the derived-peptide is then secreted by granules in sweat.

The molecular weight of the DCD full-length sequence is 9,3 kDa including the signal peptide.

The active form also named DCD-1L contains the C-terminal end from the 63 to the 110 residue and is probably created by combination of proteases in sweat under specific conditions. The cathepsin D, 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease are involved in the post-secretory processing of DCD-1L <ref>[[ J. Biol. Chem.-2006-Baechle-5406-15]], </ref>. The clivage could happen because the sweat is acidic and composed of salt concentration such as sodium, chloride, potassium and magnesium. The cathepsin D with 1,10-phenthroline-sensitive carboxypeptidase and an endoprotease showed processed DCD-1L

This form is involved in the [https://en.wikipedia.org/wiki/Innate_immune_system_ innate immune system] and protect from a variety of pathogenic microorganisms.

The Dermcidin peptide sequence has no homology with other known antimicrobial peptides. Two classes of mammalian antimicrobial peptides exist :
*[https://en.wikipedia.org/wiki/Cathelicidin_ Cathelicidins]
*[https://fr.wikipedia.org/wiki/Défensine_ Defensins] which are cationic peptides (α-defensins and β-defensins)

But, some size and structural similarities can be found with the defensin family.

== Structural highlights ==

Dermcidin is a '''channel''' composed of 3 antiparallel dimers, and has a dimension of about 8x4 nm.

* Monomer :

A monomer is 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. The residues involved are charged amino acids such as E, D and H.

* Assembly of three monomers :

The trimer is formed by salt bridges between 3 subunits. This bonds are managed again by the negatively and positively charged residues so hydrophilic residues. Polar amino acids can be localized in the bond area too. In total, 96 residues are ionizable and which are all facing toward the interior of the tunnel. However, the amino acids pointing toward the exterior are hydrophobic because they are able to interact with the acyl chain of the membrane. They play a role in the internalization in the membrane.
The bonds between monomers allow the formation of 6 lateral openings of a diameter of 1 nm. And the presence of small (such as polar amino acids) and positive residues may have an impact on the selection of ion entry.

*The zinc cofactors :

The zinc ions are fundamental as if there are not here, the DCD is no longer a channel. And the high permeability and conductance of the channel is allowed by Zn2+.

== Antimicrobial activity ==

== Related disease ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references />
1. Song, C. et al. : Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel. PNAS. 2013
2. Maren Paulmann, Thomas Arnold, Dirk Linke, Suat Özdirekcan, Annika Kopp, Thomas Gutsmann, Hubert Kalbacher, Ines Wanke, Verena J. Schuenemann, Michael Habeck, Jochen Bürck, Anne S. Ulrich and Birgit Schittek :Structure-Activity Analysis of the Dermcidin-derived Peptide DCD-1L, an Anionic Antimicrobial Peptide Present in Human Sweat
3. 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
4. H. Steffen, S. Rieg, I. Wiedemann, H. Kalbacher, M. Deeg, H.-G. Sahl, A. Peschel, F. Götz, C. Garbe, B. Schittek : Naturally Processed Dermcidin-Derived Peptides Do Not Permeabilize Bacterial Membranes and Kill Microorganisms Irrespective of Their Charge.
5. Zhang, J., Ding, W., Kuai, X., Ji, Y., Zhu, Z., Mao, Z., Wang, Z. : Dermcidin as a novel binding protein of lncRNA STCAT3 and its effect on prognosis in gastric cancer. 2018

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