Volume 9, Issue 1 (2018)                   JMBS 2018, 9(1): 47-52 | Back to browse issues page

XML Persian Abstract Print

1- Biophysics Department, Biological Sciences Faculty, Tarbiat Modares University, Tehran, Iran, Biophysics Department, Biological Sciences Faculty, Tarbiat Modares University, Nasr Bridge, Jalal-Al-Ahmad ‎Highway, Tehran, Iran , taghdir@modares.ac.ir
2- Biophysics Department, Biological Sciences Faculty, Tarbiat Modares University, Tehran, Iran
Abstract:   (7623 Views)
Aims: The Mesd is a universal inhibitor and has therapeutic effect against triple negative breast cancer. The peptide derived from carboxyl terminal, similar to protein, acts as an inhibitor of the pathway. The aim of this study was to investigate the probable binding sites of Mesd and its peptide derived from carboxyl terminal on LRP6 first and second beta-propeller domains from a structural point of view in drug design.
Materials & Methods: This experimental study was conducted, using blind and site-directed molecular docking simulation with ClusPro and Haddock and molecular dynamic simulation. The binding sites of Mesd and the peptide on the first and second beta-propeller domains of receptor LRP6 were investigated and the selected complexes were structurally analyzed.
Findings: Extensive levels of Mesd protein were found to interact with LRP6 and the levels involved in the peptide were much lower. The binding region of Mesd to LRP6 was from the carboxyl terminal. The binding region of the peptide and the protein on LRP6 was a similar region between First and Second Beta-Propeller Domains of LRP6. The RMSD and RMSF chart of the Mesd complex and its peptide was approximately the same with the first functional domain of the LRP6 co-receptor.
Conclusion: The binding region of the peptide and the protein on LRP6 is not completely similar, but according to molecular simulation of selected complexes, the pattern of the inhibition mechanism is common and emphasizes on inter domain motion control from a structural point of view. Interactive region of each ligand is similar to a region of the co-receptor, which has maximum flexibility. Molecular docking simulation of Mesd and co-receptor shows important role of carboxyl terminal of the protein to bind to LRP6.
Full-Text [PDF 691 kb]   (2892 Downloads)    
Article Type: Research Paper | Subject: Agricultural Biotechnology
Received: 2016/03/8 | Accepted: 2018/01/27 | Published: 2018/05/22

1. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. ‎‎2004;20:781-810.‎ [Link] [DOI:10.1146/annurev.cellbio.20.010403.113126]
2. Baarsma HA, Königshoff M, Gosens R. The WNT signaling pathway from ligand secretion to gene ‎transcription: Molecular mechanisms and pharmacological targets. Pharmacol Ther. 2013;138(1):66-83.‎ [Link] [DOI:10.1016/j.pharmthera.2013.01.002]
3. Polakis P. The many ways of Wnt in cancer. Curr Opin Genet Dev. 2007;17(1):45-51.‎ [Link] [DOI:10.1016/j.gde.2006.12.007]
4. Herr P, Hausmann G, Basler K. WNT secretion and signalling in human disease. Trends Mol Med. ‎‎2012;18(8):483-93.‎ [Link] [DOI:10.1016/j.molmed.2012.06.008]
5. Brown AM. Wnt signaling in breast cancer: Have we come full circle?. Breast Cancer Res. 2001;3(6):351-5.‎ [Link] [DOI:10.1186/bcr321]
6. Liu CC, Prior J, Piwnica-Worms D, Bu G. LRP6 overexpression defines a class of breast cancer subtype and ‎is a target for therapy. Proc Natl Acad Sci USA. 2010;107(11):5136-41.‎ [Link] [DOI:10.1073/pnas.0911220107]
7. Howe LR, Brown AM. Wnt signaling and breast cancer. Cancer Biol Ther. 2004;3(1):36-41.‎ [Link] [DOI:10.4161/cbt.3.1.561]
8. Benhaj K, Akcali KC, Ozturk M. Redundant expression of canonical Wnt ligands in human breast cancer ‎cell lines. Oncol Rep. 2006;15(3):701-7.‎ [Link]
9. Edwards BK, Noone AM, Mariotto AB, Simard EP, Boscoe FP Henley SJ, et al. Annual report to the nation ‎on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among ‎persons with lung, colorectal, breast, or prostate cancer. Cancer. 2014;120(9):1290-314.‎ [Link]
10. Hsieh JC, Lee L, Zhang L, Wefer S, Brown K, DeRossi C, et al. Mesd encodes an LRP5/6 chaperone ‎essential for specification of mouse embryonic polarity. Cell. 2003;112(3):355-67.‎ [Link]
11. Lu W, Liu CC, Thottassery JV, Bu G, Li Y. Mesd is a universal inhibitor of Wnt coreceptors LRP5 and LRP6 ‎and blocks Wnt/β-catenin signaling in cancer cells. Biochemistry. 2010;49(22):4635-43.‎ [Link] [DOI:10.1021/bi1001486]
12. Deshpande N, Addess KJ, Bluhm WF, Merino-Ott JC, Townsend-Merino W, Zhang Q, et al. The RCSB ‎protein data bank: A redesigned query system and relational database based on the mmCIF schema. Nucleic ‎Acids Res. 2005;33(Database issue):D233-7.‎ [Link]
13. Vriend G. What if: A molecular modeling and drug design program. J Mol Graph. 1990;8(1):52-6.‎ [Link] [DOI:10.1016/0263-7855(90)80070-V]
14. Haile JM. Molecular dynamics simulation: Elementary methods. New York: Wiley; 1992.‎ [Link]
15. ‎Case DA, Darden TA, Cheatham TE, Simmerling CL, Wang RE, Duke RE, et al. Amber 10 user's manual ‎‎[Internet]. California: University of California; 2008 [cited 2018 May 25]. Available from: ‎http://glycam.org/legacy_courses/2010/8330/pdfs/Amber10i.pdf.‎ [Link]
16. Liu CC, Pearson C, Bu G. Cooperative folding and ligand-binding properties of LRP6 β-propeller domains. ‎J Biol Chem. 2009;284(22):15299-307.‎ [Link] [DOI:10.1074/jbc.M807285200]
17. Bourhis E, Tam C, Franke Y, Bazan JF, Ernst J, Hwang J, et al. Reconstitution of a frizzled8.Wnt3a.LRP6 ‎signaling complex reveals multiple Wnt and Dkk1 binding sites on LRP6. J Biol Chem. 2010;285(12):9172-9.‎ [Link]
18. Lin C, Lu W, Zhang W, Londo-o-Joshi AI, Buchsbaum DJ, Bu G, et al. The C-terminal region Mesd peptide ‎mimics full-length Mesd and acts as an inhibitor of Wnt/β-catenin signaling in cancer cells. PloS One. ‎‎2013;8(2):e58102.‎ [Link]
19. Köhler C, Lighthouse JK, Werther T, Andersen OM, Diehl A, Schmieder P, et al. The structure of ‎MESD45–184 brings light into the mechanism of LDLR family folding. Structure. 2011;19(3):337-48.‎ [Link]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.