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This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115.
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Dermcidin is a Human antimicrobial, anionic and ion membrane channel (2YMK) discovered in 2001 based on 6 dermcidin antimicrobial peptides of 110 amino acids present in sweat. Dermcidin expands with other antimicrobial peptides the natural role of the skin to form a barrier to non-human invaders. These peptides, encoded by the DCD gene, play a role in the host defense system as a trimeric channel and thus, are able to prevent infection after injuries or any skin disorders. Scientists are focused on this molecule due to his charge particularity and since antibiotic resistances have been observed.

Contents

Homology

The dermcidin peptide sequence has no homology with other known antimicrobial peptide(shortened to AMP). There are two types of AMP, the anionic antimicrobial peptide (AAMP) and the cationic one (CAMP). These two AMP are completing themselves as they 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:

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

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 eccrine sweat glands within the dermis of the skin. The molecular weight of the DCD full-length sequence is 9.3 kDa including the signal peptide (in italic). The peptide is then secreted by granules in sweat and transported to the epidermal surface.

DCD full-length sequence: MRFMTLLFLTALAGALVCAYDPEAASAPGSGNPCHEASAAQKENAGEDPGLARQAPKPRKQRSSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSVL [1]

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

Structural highlights

Structure of the Dermicidin in the PDB.

Drag the structure with the mouse to rotate

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

Monomer

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

Assembly of three monomers

The trimer is formed by between 3 subunits. These bonds based on the zipper structure are managed again by the negatively (in blue) and positively (in red) charged residues, hence hydrophilic residues. (in pink) amino acids can be also localized in the bond area neglecting positive amino acids. In total, 96 residues are ionizable which are all facing toward the interior of the tunnel forming  : I,II,III,II,I as they are alternating negative (in blue) and positive (in red) charges.[3] They create a channel with an overall charge of -12 because DCD-1L peptide is -2.

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

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

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+.[3]

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 [1].

The overall negatively charged DCD-1L is a one amino acid longer DCD-1 and shows beside the antimicrobial activity against Escherichia coli, Staphylococcus aureus and Enterococcus faecalis additional high fungicidal activity on Candida albicans.[1] 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.[5] However, some authors are not in agreement on this with each other[3] since it was also detected that DCD-1L creates ion channels into the bacterial membranes promoted by Zn2+.[6]

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.[2]

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.[7]

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 [6].

Cancer related diseases

Dermcidin is related to certain cancer diseases such as prostatic cancer[8], lung cancer[9][10], melanoma[11][12], breast cancer[13][14] and hepatocellular carcinoma.[15][16] 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 therefore could be used as clinical predictors for gastric cancer development.[17] Often times, dermcidin is in the discussion to function as a general biomarker for the above mentioned diseases but also being a potential target for anticancer drugs such as seriniquinone.[12] The anticancer effect could derive from direct interaction or from protein complexes linked via disulfide bonds to DCD, which was already shown for Hsp70. In the survival-promoting peptide area of dermcidin, GNPCH is considered to be an ATP-dependent binding-site for Hsp70.[18]

References

  1. ↑ 1.0 1.1 1.2 1.3 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" Nature Immunology 2, no. 12 (December, 2001): 1133-37. https://doi.org/10.1038/ni732
  2. ↑ 2.0 2.1 Daniel Baechle, Thomas Flad, Alexander Cansier, Heiko Steffen, Birgit Schittek, Jonathan Tolson, Timo Herrmann, Hassan Dihazi􏰀, Alexander Beck, Gerhard A. Mueller􏰀, Margret Mueller, Stefan Stevanovic, Claus Garbe, Claudia A. Mueller, and Hubert Kalbacher. "Cathepsin D Is Present in Human Eccrine Sweat and Involved in the Postsecretory Processing of the Antimicrobial Peptide DCD-1L" J. Biol. Chem. 281, no. 9 (March 3, 2006): 5406-15. https://doi.org/10.1074/jbc.M504670200
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Song, C. et al. "Crystal Structure and Functional Mechanism of a Human Antimicrobial Membrane Channel." PNAS 110, no. 12 (March 19, 2013): 4586-591. https://doi.org/10.1073/pnas.1214739110
  4. ↑ Van Sang Nguyen, Kang Wei Tan, Karthik Ramesh, Fook Tim Chew & Yu Keung Mok. "Structural basis for the bacterial membrane insertion of dermcidin" Nature Scientific reports 7 : 13923 (2017). https://doi.org/10.1038/s41598-017-13600-z
  5. ↑ 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
  6. ↑ 6.0 6.1 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 12.0 12.1 Trzoss, L., Fukuda, T., Costa-Lotufo, L.V., Jimenez, P., La Clair, J.J., Fenical, W., 2014. Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin. Proceedings of the National Academy of Sciences 111, 14687–14692. https://doi.org/10.1073/pnas.1410932111
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
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