Dermcidin Explained
Dermcidin is a protein with 110 amino acids that in humans is encoded by the DCD gene.[1] [2] The full-length protein produces derived peptides as proteolysis-inducing factor (PIF) and other anti-microbial peptides, secreted by human eccrine sweat glands onto the skin as a part of the innate host defense of the immune system. PIF is involved in muscular proteolysis.
Function
Dermcidin is a secreted protein that is subsequently processed into mature peptides of distinct biological activities. The C-terminal peptide is constitutively expressed in sweat and has antibacterial and antifungal activities. The N-terminal peptide, also known as diffusible survival evasion peptide, promotes neural cell survival under conditions of severe oxidative stress. A glycosylated form of the N-terminal peptide may be associated with cachexia (muscle wasting) in cancer patients.[2]
Survival evasion peptide Antimicrobial peptideYDPEAASAPGSGNPCHEASAAQKENAGEDPGLARQAPKPRKQRSSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSVLThe C-terminal precursor DCD-1L is a 48 residue peptide that shows partial helicity in solution, as evidenced by the determination of its solution structure by
NMR and
CD-spectroscopy. The full length precursor is processed by undetermined proteases present in human sweat, to form several shorter peptides that show variable antimicrobial activity, named according to their C-terminal triplet of
amino acids and their residue length. One such active peptide is SSL25, which shows a 2-fold increase in activity against
E. coli compared to DCD-1L.
[3] DCD-1L SSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSVL DCD-1 SSLLEKGLDGAKKAVGGLGKLGKDAVEDLESVGKGAVHDVKDVLDSV SSL25 SSLLEKGLDGAKKAVGGLGKLGKDA
Mechanism
The crystal structure of dermcidin has been solved in solution to reveal a hexameric helix-bundle, mediated by Zn ion binding.[4] This is observed to form a tilted channel in membranes under computational examination by molecular dynamics simulations, and one suggested mechanism of antimicrobial action inferred from this observation is by ion gradient decoupling across biological membranes. This is supported by concurrent observations in experimental studies of a voltage dependent depolarization of lipid bilayers.
Further reading
- Todorov P, Cariuk P, McDevitt T . Characterization of a cancer cachectic factor. . Nature . 379 . 6567 . 739–42 . 1996 . 8602222 . 10.1038/379739a0 . 1996Natur.379..739T . 4331928 . etal.
- Todorov PT, Deacon M, Tisdale MJ . Structural analysis of a tumor-produced sulfated glycoprotein capable of initiating muscle protein degradation. . J. Biol. Chem. . 272 . 19 . 12279–88 . 1997 . 9139670 . 10.1074/jbc.272.19.12279 . free .
- Cunningham TJ, Hodge L, Speicher D . Identification of a survival-promoting peptide in medium conditioned by oxidatively stressed cell lines of nervous system origin. . J. Neurosci. . 18 . 18 . 7047–60 . 1998 . 9736629 . 10.1523/JNEUROSCI.18-18-07047.1998. 6793258 . etal. free .
- Cunningham TJ, Jing H, Wang Y, Hodge L . Calreticulin binding and other biological activities of survival peptide Y-P30 including effects of systemic treatment of rats. . Exp. Neurol. . 163 . 2 . 457–68 . 2000 . 10833321 . 10.1006/exnr.2000.7390 . 22279800 .
- Cunningham TJ, Jing H, Akerblom I . Identification of the human cDNA for new survival/evasion peptide (DSEP): studies in vitro and in vivo of overexpression by neural cells. . Exp. Neurol. . 177 . 1 . 32–9 . 2002 . 12429208 . 10.1006/exnr.2002.7979 . 11829104 . etal.
- Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
- Porter D, Weremowicz S, Chin K . A neural survival factor is a candidate oncogene in breast cancer. . Proc. Natl. Acad. Sci. U.S.A. . 100 . 19 . 10931–6 . 2003 . 12953101 . 10.1073/pnas.1932980100 . 196905 . 2003PNAS..10010931P . etal. free .
- Zhang Z, Henzel WJ . Signal peptide prediction based on analysis of experimentally verified cleavage sites. . Protein Sci. . 13 . 10 . 2819–24 . 2005 . 15340161 . 10.1110/ps.04682504 . 2286551 .
- Suzuki Y, Yamashita R, Shirota M . Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. . Genome Res. . 14 . 9 . 1711–8 . 2004 . 15342556 . 10.1101/gr.2435604 . 515316 . etal.
- Monitto CL, Dong SM, Jen J, Sidransky D . Characterization of a human homologue of proteolysis-inducing factor and its role in cancer cachexia. . Clin. Cancer Res. . 10 . 17 . 5862–9 . 2005 . 15355918 . 10.1158/1078-0432.CCR-04-0435 . free .
- Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
- Lai YP, Peng YF, Zuo Y . Functional and structural characterization of recombinant dermicidin-1L, a human antimicrobial peptide. . Biochem. Biophys. Res. Commun. . 328 . 1 . 243–50 . 2005 . 15670776 . 10.1016/j.bbrc.2004.12.143 . etal.
- Rieg S, Steffen H, Seeber S . Deficiency of dermicidin-derived antimicrobial peptides in sweat of patients with atopic dermatitis correlates with an impaired innate defense of human skin in vivo. . J. Immunol. . 174 . 12 . 8003–10 . 2005 . 15944307 . 10.4049/jimmunol.174.12.8003. etal. free .
- Watchorn TM, Dowidar N, Dejong CH . The cachectic mediator proteolysis inducing factor activates NF-kappaB and STAT3 in human Kupffer cells and monocytes. . Int. J. Oncol. . 27 . 4 . 1105–11 . 2006 . 16142329 . 10.3892/ijo.27.4.1105. etal.
- Lowrie AG, Wigmore SJ, Wright DJ . dermicidin expression in hepatic cells improves survival without N-glycosylation, but requires asparagine residues. . Br. J. Cancer . 94 . 11 . 1663–71 . 2006 . 16685272 . 10.1038/sj.bjc.6603148 . 2361319 . etal.
- Ewing RM, Chu P, Elisma F . Large-scale mapping of human protein-protein interactions by mass spectrometry. . Mol. Syst. Biol. . 3 . 1. 89 . 2007 . 17353931 . 10.1038/msb4100134 . 1847948 . etal.
- Frum R, Busby SA, Ramamoorthy M . HDM2-binding partners: interaction with translation elongation factor EF1alpha. . J. Proteome Res. . 6 . 4 . 1410–7 . 2007 . 17373842 . 10.1021/pr060584p . etal . 4626875.
- Lee Motoyama JP, Kim-Motoyama H, Kim P . Identification of dermicidin in human gestational tissue and characterization of its proteolytic activity. . Biochem. Biophys. Res. Commun. . 357 . 4 . 828–33 . 2007 . 17448443 . 10.1016/j.bbrc.2007.03.112 . etal.
Notes and References
- Schittek B, Hipfel R, Sauer B, Bauer J, Kalbacher H, Stevanovic S, Schirle M, Schroeder K, Blin N, Meier F, Rassner G, Garbe C . Dermicidin: a novel human antibiotic peptide secreted by sweat glands . Nat Immunol . 2 . 12 . 1133–7 . Nov 2001 . 11694882 . 10.1038/ni732 . 26126901 .
- Web site: Entrez Gene: DCD dermicidin.
- Baechle D, Flad T, Cansier A . Cathepsin D is present in human eccrine sweat and involved in the postsecretory processing of the antimicrobial peptide DCD-1L. . J. Biol. Chem. . 281 . 9 . 5406–15 . 2006 . 16354654 . 10.1074/jbc.M504670200 . etal. free .
- Song, Chen . Weichbrodt, Conrad . Salnikov, Evgeniy S . Dynowski, Marek . Forsberg, Björn O . Bechinger, Burkhard . Steinem, Claudia . de Groot, Bert L . Zachariae, Ulrich . Zeth, Kornelius . Crystal structure and functional mechanism of a human antimicrobial membrane channel . PNAS . 110 . 12 . 4586–91. Feb 2013 . 23426625 . 3607029. 10.1073/pnas.1214739110 . 2013PNAS..110.4586S . free .
