Molecular Dynamics Optimization of a Computational Model of TACE and its Substrate Peptide

Abstract:

Tumor necrosis factor-alpha converting enzyme (TACE) is a very important membrane-bound proteinase, and it can cut a lot of membrane proteins to their released form. Many of the substrates of TACE are critical protein factors, such as IL-6, TNF-alpha, EGF receptor. Therefore, TACE has been a hopeful drug targets in many diseases. However, selective inhibitors against TACE with high specificity has yet been developed successfully, partly due to the lack of the understanding of the TACE substrate interaction details. To solve this problem, here we build a computational complex model of the TACE catalytic domain and its substrate peptide using the protein design software Rosetta. To further optimize the complex model, molecular dynamics analysis was performed in NAMD with explicit water molecules. The result showed that our complex model is a pretty reliable intermediate model for TACE and its peptide substrate. This complex model could be very useful for further study of the substrate specificity and selectivity of TACE.

• Periodical: Advanced Materials Research (Volume 680)
• Pages: 131-136
• DOI: https://doi.org/10.4028/www.scientific.net/AMR.680.131
• Online since: April 2013
• Authors: Liu Sen, Xiao Hong Ma
• Keywords: ADAM17, Molecular Modeling, TNF-Alpha, TNF-Alpha Converting Enzyme

References

[1] X. Li, Inhibitory role of TACE/ADAM17 cytotail in protein ectodomain shedding, WJBC, vol. 2, no. 11, p.246, (2011).

DOI: 10.4331/wjbc.v2.i11.246

[2] X. Li, L. Pérez, Z. Pan, and H. Fan, The transmembrane domain of TACE regulates protein ectodomain shedding, Cell Res, vol. 17, no. 12, p.985–998, Dec. (2007).

DOI: 10.1038/cr.2007.98

[3] P. Saftig and K. Reiss, The A Disintegrin And Metalloproteases' ADAM10 and ADAM17: novel drug targets with therapeutic potential, Eur. J. Cell Biol., vol. 90, no. 6, p.527–535, Jun. (2011).

DOI: 10.1016/j.ejcb.2010.11.005

[4] K. P. Fong, C. Barry, A. N. Tran, E. A. Traxler, K. M. Wannemacher, H. -Y. Tang, K. D. Speicher, I. A. Blair, D. W. Speicher, T. Grosser, and L. F. Brass, Deciphering the human platelet sheddome., Blood, vol. 117, no. 1, pp. e15–26, Jan. (2011).

DOI: 10.1182/blood-2010-05-283838

[5] S. F. Lichtenthaler, Sheddase Gets Guidance, Science, vol. 335, no. 6065, p.179–180, Jan. (2012).

DOI: 10.1126/science.1216815

[6] J. Scheller, A. Chalaris, C. Garbers, and S. Rose-John, ADAM17: a molecular switch to control inflammation and tissue regeneration., Trends Immunol., vol. 32, no. 8, p.380–387, Aug. (2011).

DOI: 10.1016/j.it.2011.05.005

[7] A. Baumgart, S. Seidl, P. Vlachou, L. Michel, N. Mitova, N. Schatz, K. Specht, I. Koch, T. Schuster, R. Grundler, M. Kremer, F. Fend, J. T. Siveke, C. Peschel, J. Duyster, and T. Dechow, ADAM17 Regulates Epidermal Growth Factor Receptor Expression through the Activation of Notch1 in Non-Small Cell Lung Cancer, Cancer Research, vol. 70, no. 13, p.5368–5378, Jun. (2010).

DOI: 10.1158/0008-5472.can-09-3763

[8] M. Gooz, ADAM-17: the enzyme that does it all, Critical Reviews in Biochemistry and Molecular Biology, vol. 45, no. 2, p.146–169, Apr. (2010).

DOI: 10.3109/10409231003628015

[9] J. Arribas and C. Esselens, ADAM17 as a therapeutic target in multiple diseases., Curr. Pharm. Des., vol. 15, no. 20, p.2319–2335, (2009).

DOI: 10.2174/138161209788682398

[10] P. E. Gonzales, A. Solomon, A. B. Miller, M. A. Leesnitzer, I. Sagi, and M. E. Milla, Inhibition of the tumor necrosis factor-alpha-converting enzyme by its pro domain., Journal of Biological Chemistry, vol. 279, no. 30, p.31638–31645, Jul. (2004).

DOI: 10.1074/jbc.m401311200

[11] S. DasGupta, P. R. Murumkar, R. Giridhar, and M. R. Yadav, Current perspective of TACE inhibitors: A review, Bioorganic & Medicinal Chemistry, vol. 17, no. 2, p.444–459, Jan. (2009).

DOI: 10.1016/j.bmc.2008.11.067

[12] I. H. Tarner, U. Müller-Ladner, and S. Gay, Emerging targets of biologic therapies for rheumatoid arthritis, Nat Clin Pract Rheumatol, vol. 3, no. 6, p.336–345, Jun. (2007).

DOI: 10.1038/ncprheum0506

[13] K. Maskos, C. Fernandez-Catalan, R. Huber, G. P. Bourenkov, H. Bartunik, G. A. Ellestad, P. Reddy, M. F. Wolfson, C. T. Rauch, and B. J. Castner, Crystal structure of the catalytic domain of human tumor necrosis factor-α-converting enzyme, Proc. Natl. Acad. Sci. U.S.A., vol. 95, no. 7, p.3408, (1998).

DOI: 10.1073/pnas.95.7.3408

[14] B. Raveh, N. London, L. Zimmerman, and O. Schueler-Furman, Rosetta FlexPepDock ab-initio: simultaneous folding, docking and refinement of peptides onto their receptors., PLoS ONE, vol. 6, no. 4, p. e18934, (2011).

DOI: 10.1371/journal.pone.0018934

[15] J. C. Phillips, R. Braun, W. Wang, J. Gumbart, E. Tajkhorshid, E. Villa, C. Chipot, R. D. Skeel, L. Kalé, and K. Schulten, Scalable molecular dynamics with NAMD., J. Comput. Chem., vol. 26, no. 16, p.1781–1802, Dec. (2005).

DOI: 10.1002/jcc.20289

[16] W. Humphrey, A. Dalke, and K. Schulten, VMD: visual molecular dynamics., J Mol Graph, vol. 14, no. 1, p.33–8– 27–8, Feb. (1996).

DOI: 10.1016/0263-7855(96)00018-5