The Intrinsic Pepsin Resistance of Interleukin-8 Can Be Explained from a Combined Bioinformatical and Experimental Approach
Authors: 
Gerd Anders, Ulrich Hassiepen, Stephan Theisgen, Stephan Heymann, Lionel Muller, Tania Panigada, Daniel Huster, Sergey A. SamsonovAuthors Info & Claims
Pages 300 - 308
Abstract
Interleukin-8 IL-8, CXCL8 is a neutrophil chemotactic factor belonging to the family of chemokines. IL-8 was shown to resist pepsin cleavage displaying its high resistance to this protease. However, the molecular mechanisms underlying this resistance are not fully understood. Using our in-house database containing the data on three-dimensional arrangements of secondary structure elements from the whole Protein Data Bank, we found a striking structural similarity between IL-8 and pepsin inhibitor-3. Such similarity could play a key role in understanding IL-8 resistance to the protease pepsin. To support this hypothesis, we applied pepsin assays confirming that intact IL-8 is not degraded by pepsin in comparison to IL-8 in a denaturated state. Applying 1H-15N Heteronuclear Single Quantum Coherence NMR measurements, we determined the putative regions at IL-8 that are potentially responsible for interactions with the pepsin. The results obtained in this work contribute to the understanding of the resistance of IL-8 to pepsin proteolysis in terms of its structural properties.
References
[1]
M. Baggiolini, A. Walz, and S. L. Kunkel, "Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils," J. Clin. Investigation, vol. 84, no. 4, pp. 1045-1049, Oct. 1989.
[2]
W. Schnitzel, U. Mondschein, and J. Besemer, "Monomer-dimer equilibria of interleukin-8 and neutrophil-activating peptide 2. Evidence for IL-8 binding as a dimer and oligomer to IL-8 receptor B," J. Leukocyte Biol., vol. 55, no. 6, pp. 763-770, Jun. 1994.
[3]
A. Maheshwari, W. Lu, W. C. Guida, R. D. Christensen, and D. A. Calhoun, "IL-8/CXC ligand 8 survives neonatal gastric digestion as a result of intrinsic aspartyl proteinase resistance," Pediatric Res., vol. 57, no. 3, pp. 438-444, Mar. 2005.
[4]
K. Girdwood and C. Berry, "The disulphide bond arrangement in the major pepsin inhibitor PI-3 of Ascaris suum," FEBS Lett., vol. 474, no. 2/3, pp. 253-255, Jun. 2000.
[5]
D. R. Davies, "The structure and function of the aspartic proteinases," Annu. Rev. Biophys. Biophys. Chem., vol. 19, pp. 189- 215, Jun. 1990.
[6]
J. S. Fruton, "A history of pepsin and related enzymes," Quarterly Rev. Biol., vol. 77, no. 2, pp. 127-147, Jun. 2002.
[7]
B. M. Dunn, "Structure and mechanism of the pepsin-like family of aspartic peptidases," Chem. Rev., vol. 102, no. 12, pp. 4431-4458, Dec. 2002.
[8]
K. K. S. Ng, et al., "Structural basis for the inhibition of porcine pepsin by Ascaris pepsin inhibitor-3," Nat. Struct. Biol., vol. 7, no. 8, pp. 653-657, Aug. 2000.
[9]
J. Willenbücher, W. Höfle, and R. Lucius, "The filarial antigens Av33/Ov33-3 show striking similarities to the major pepsin inhibitor from Ascaris suum," Mol. Biochem. Parasitology, vol. 57, no. 2, pp. 349-352, Feb. 1993.
[10]
M. Li, et al., "The aspartic proteinase from Saccharomyces cerevisiae folds its own inhibitor into a helix," Nat. Struct. Biol., vol. 7, no. 2, pp. 113-117, Feb. 2000.
[11]
G. M. Abu-Erreish and R. J. Peanasky, "Pepsin inhibitors from Ascaris lumbricoides. Isolation, purification, and some properties," J. Biol. Chem., vol. 249, no. 5, pp. 1558-1565, Mar. 1974.
[12]
T. Kageyama, "Molecular cloning, expression and characterization of an Ascaris inhibitor for pepsin and cathepsin E," Eur. J. Biochem., vol. 253, no. 3, pp. 804-809, May 1998.
[13]
N. S. A. Krushna, C. Shiny, G. Manokaran, S. Elango, and R. B. Narayanan, "Immune responses to recombinant Brugia malayi pepsin inhibitor homolog (Bm-33) in patients with human lymphotactic filariaisis," Parasitology Res., vol. 108, no. 2, pp. 407- 415, Feb. 2011.
[14]
M. J. Valler, J. Kay, T. Aoyagi, and B. M. Dunn, "The interaction of aspartic proteinases with naturally-occurring inhibitors from actinomycetes and Ascaris lumbricoides," J. Enzyme Inhibition, vol. 1, no. 1, pp. 77-82, 1985.
[15]
F. D. Finkelman, et al., "Cytokine regulation of host defense against parasitic gastrointestinal nematodes: Lessons from studies with rodent models," Annu. Rev. Immunology, vol. 15, pp. 505-533, Apr. 1997.
[16]
W. C. Gause, J. F. Urban Jr., and M. J. Stadecker, "The immune response to parasitic helminths: Insights from murine models," Trends Immunology, vol. 24, no. 5, pp. 269-277, May 2003.
[17]
C. Bazzocchi, C. Genchi, S. Paltrinieri, C. Lecchi, M. Mortarino, and C. Bandi, "Immunological role of the endosymbionts of dirofilaria immitis: The wolbachia surface protein activates canine neutrophils with production of IL-8," Veterinary Parasitology, vol. 117, no. 1/2, pp. 73-83, Nov. 2003.
[18]
L. Proudfoot, "Parasitic helminths tip the balance: Potential anti-inflammatory therapies," Immunology, vol. 113, no. 4, pp. 438-440, Dec. 2004.
[19]
F. H. Falcone, A. G. Rossi, R. Sharkey, A. P. Brown, D. I. Pritchard, and R. M. Maizels, "Ascaris suum-derived products induce human neutrophil activation via a G protein-coupled receptor that interacts with the interleukin-8 receptor pathway," Infection Immunity, vol. 69, no. 6, pp. 4007-4018, Jun. 2001.
[20]
H. J. Wolfson and I. Rigoutsos, "Geometric hashing: An overview," IEEE Trans. Comput. Sci. Eng., vol. 4, no. 4, pp. 10-21, Apr. 1997. [Online]. Available: http://www.cse.unr.edu/~mircea/Teaching/cs485_685/Readings/Wolfson97.pdf
[21]
X. Pennec and N. Ayache, "An O(n2) algorithm for 3D substructure matching of proteins," in Proc. 1st Int. Workshop Shape Pattern Matching Comput. Biol., 1994, pp. 25-40.
[22]
A. C. Wallace, N. Borkakoti, and J. M. Thornton, "TESS: A geometric hashing algorithm for deriving 3D coordinate templates for searching structural databases. Application to enzyme active sites," Protein Sci., vol. 6, no. 11, pp. 2308-2323, Nov. 1997.
[23]
X. Pennec and N. Ayache, "A geometric algorithm to find small but highly similar 3D substructures in proteins," Bioinf., vol. 14, no. 6, pp. 516-522, 1998.
[24]
L. Holm and C. Sander, "3-D lookup: Fast protein structure database searches at 90% reliability," in Proc. Int. Conf. Intell. Syst. Mol. Biol., 1995, vol. 3, pp. 179-187.
[25]
E. M. Mitchell, P. J. Artymiuk, D. W. Rice, and P. Willett, "Use of techniques derived from graph theory to compare secondary structure motifs in proteins," J. Mol. Biol., vol. 212, no. 1, pp. 151- 166, Mar. 1990.
[26]
H. M. Grindley, P. J. Artymiuk, D. W. Rice, and P. Willett, "Identification of tertiary structure resemblance in proteins using a maximal common subgraph isomorphism algorithm," J. Mol. Biol., vol. 229, no. 3, pp. 707-721, Feb. 1993.
[27]
K. Mizuguchi and N. Go, "Comparison of spatial arrangements of secondary structural elements in proteins," Protein Eng., vol. 8, no. 4, pp. 353-362, Apr. 1995.
[28]
I. Koch, T. Lengauer, and E. Wanke, "An algorithm for finding maximal common subtopologies in a set of protein structures," J. Comput. Biol., vol. 3, no. 2, pp. 289-306, Summer 1996.
[29]
E. J. Gardiner, P. J. Artymiuk, and P. Willett, "Clique-detection algorithms for matching three-dimensional molecular structures," J. Mol. Graph. Model., vol. 15, no. 4, pp. 245-253, Aug. 1997.
[30]
A. Harrison, F. Pearl, R. Mott, J. Thornton, and C. Orengo, "Quantifying the similarities within fold space," J. Mol. Biol., vol. 323, no. 5, pp. 909-926, Nov. 2002
[31]
N. Weskamp, D. Kuhn, E. Hüllermeier, and G. Klebe, "Efficient similarity search in protein structure database by k-clique hashing," Bioinf., vol. 20, no. 10, pp. 1522-1526, Jul. 2004.
[32]
B. Kolbeck, P. May, T. Schmidt-Goenner, T. Steinke, and E.-W. Knapp, "Connectivity independent protein-structure alignment: A hierarchical approach," BMC Bioinf., vol. 7, Nov. 2006, Art. no. 510.
[33]
S. Butenko and W. E. Wilhelm, "Clique-detection models in computational biochemistry and genomics," Eur. J. Oper. Res., vol. 173, no. 1, pp. 1-17, Aug. 2006.
[34]
P. Willett, "Searching for pharmacophoric patterns in databases of three-dimensional chemical structures," J. Mol. Recognit., vol. 8, no. 5, pp. 290-303, Sep./Oct. 1995.
[35]
J. D. Westbrook, N. Ito, H. Nakamura, K. Henrick, and H. M. Berman, "PDBML: The representation of archival macromolecular structure data in XML," Bioinf., vol. 21, no. 7, pp. 988-992, Apr. 2005.
[36]
H. Berman, K. Henrick, H. Nakamura, and J. L. Markley, "The worldwide protein data bank (wwPDB): Ensuring a single, uniform archive of the PDB data," Nucleic Acids Res., vol. 35, pp. D301-D303, Jan. 2007.
[37]
G. Anders and M. Nicola, "Managing the protein data bank with DB2 pureXML," developerWorks, 2011. [Online]. Available: http://www.ibm.com/developerworks/data/library/techarticle/dm-1109proteindatadb2purexml/
[38]
W. Kabsch and C. Sander, "Dictionary of protein secondary structure: Pattern recognition of hydrogen-bonded and geometrical features," Biopolymers, vol. 22, no. 12, pp. 2577-2637, Dec. 1983.
[39]
J. Martin, G. Letellier, A. Marin, J.-F. Taly, A. G. de Breveren, and J.-F. Gibrat, "Protein secondary structure assignment revisited: A detailed analysis of different assignment methods," BMC Struct. Biol., vol. 5, Sep. 2005, Art. no. 17.
[40]
S. Niskanen and P. R. J. Østergård, "Cliquer user's guide, version 1.0," Commun. Laboratory, Helsinki Univ. Technol., Espoo, Finland, Tech. Rep. T48, 2003.
[41]
K. Doering, G. Meder, M. Hinnenberger, J. Woelcke, L. M. Mayr, and U. Hassiepen, "A fluorescence lifetime-based assay for protease inhibitor profiling on kallikrein 7," J. Biomol. Screen., vol. 14, no. 1, pp. 1-9, Jan. 2009.
[42]
T. Kageyama, "Pepsinogens, progastricsins, and prochymosins: Structure, function, evolution, and development," Cell Mol. Life Sci., vol. 59, no. 2, pp. 288-306, Feb. 2002.
[43]
A. Maheshwari, et al., "Interleukin-8/CXCL8 forms an autocrine loop in fetal intestinal mucosa," Pediatric Res., vol. 56, no. 2, pp. 240-249, Aug. 2004.
[44]
A. R. Sielecki, A. A. Fedorov, A. Boodhoo, N. S. Andreeva, and M. N. G. James, "Molecular and crystal structures of monoclinic porcine pepsin refined at 1.8 Å resolution," J. Mol. Biol., vol. 214, no. 1, pp. 143-170, Jul. 1990.
[45]
M. Fujinaga, M. M. Chernaia, N. I. Tarasova, S. C. Mosimann, and M. N. G. James, "Crystal structure of human pepsin and its complex with pepstatin," Protein Sci., vol. 4, no. 5, pp. 960-972, May 1995.
[46]
E. Gasteiger, et al., "Protein identification and analysis tools on the ExPASy server," The Proteomics Protocols Handbook, J. M. Walker, Ed., Humana Press, New York, pp. 571-607, 2005.
[47]
A. Pichert, et al., "Characterization of the interaction of interleukin- 8 with glycosaminoglycans by solution NMR spectroscopy and molecular modelling," Glycobiology, vol. 22, no. 1, pp. 134- 145, Jan. 2012.
[48]
E. S. Seo, et al., "Interaction of human ß-defensin 2 (HBD2) with glycosaminoglycans," Biochemistry, vol. 49, no. 49, pp. 10486- 10495, Dec. 2010.
[49]
Consortium UniProt, "UniProt: A hub for protein information," Nucleic Acids Res., vol. 43, pp. D204-D12, Jan. 2015.
[50]
M. Fujinaga, M. M. Cherney, N. I. Tarasova, P. A. Bartlett, J. E. Hanson, and M. N. G. James, "Structural study of the complex between human pepsin and a phosphorus-containing peptidic transition-state analog," Acta Crystallographic D Biol. Crystallographic, vol. 56, no. Pt. 3, pp. 272-279, Mar. 2000.
[51]
R.E. Moose, et al., "Analysis of binding interactions of pepsin inhibitor-3 to mammalian and malarial aspartic proteases," Biochemistry, vol. 46, no. 49, pp. 14198-14205, Dec. 2007.
- The Intrinsic Pepsin Resistance of Interleukin-8 Can Be Explained from a Combined Bioinformatical and Experimental Approach
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Published: 01 January 2018
Published in TCBB Volume 15, Issue 1
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