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Computational Methods Involved in Evaluating the Toxicity of the Reproductive Toxicants in Sertoli Cell

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Sertoli Cells

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1748))

Abstract

The Sertoli cell, the somatic component of seminiferous tubule, provides nutritional support and immunological protection and supports overall growth and division of germ cells. Cytoskeletons, junction proteins, and kinases in Sertoli cells are prime targets for reproductive toxicants and other environmental contaminants. Among the varied targets, the kinases that are crucial for regulating varied activities in spermatogenesis such as assembly/disassembly of blood-testis barrier and apical ES and those that are involved in conferring polarity are highly targeted. In an attempt to study the effect of toxicants on these kinases, the present chapter deals with computational methodology concerning their three-dimensional structure prediction, identification of inhibitors, and understanding of conformational changes induced by these inhibitors.

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References

  1. Parvinen M (1982) Regulation of the seminiferous epithelium. Endocr Rev 3(4):404–417. https://doi.org/10.1210/edrv-3-4-404

    Article  CAS  PubMed  Google Scholar 

  2. Weber JE, Russell LD, Wong V, Peterson RN (1983) Three-dimensional reconstruction of a rat stage V Sertoli cell: II. Morphometry of Sertoli--Sertoli and Sertoli--germ-cell relationships. Am J Anat 167(2):163–179. https://doi.org/10.1002/aja.1001670203

    Article  CAS  PubMed  Google Scholar 

  3. Mital P, Kaur G, Dufour JM (2010) Immunoprotective sertoli cells: making allogeneic and xenogeneic transplantation feasible. Reproduction 139(3):495–504. https://doi.org/10.1530/REP-09-0384

    Article  CAS  PubMed  Google Scholar 

  4. Mruk DD, Cheng CY (2004) Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 25(5):747–806. https://doi.org/10.1210/er.2003-0022

    Article  CAS  PubMed  Google Scholar 

  5. Sylvester SR, Griswold MD (1994) The testicular iron shuttle: a “nurse” function of the Sertoli cells. J Androl 15(5):381–385

    CAS  PubMed  Google Scholar 

  6. Franca LR, Hess RA, Dufour JM, Hofmann MC, Griswold MD (2016) The Sertoli cell: one hundred fifty years of beauty and plasticity. Andrology 4(2):189–212. https://doi.org/10.1111/andr.12165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Oatley MJ, Racicot KE, Oatley JM (2011) Sertoli cells dictate spermatogonial stem cell niches in the mouse testis. Biol Reprod 84(4):639–645. https://doi.org/10.1095/biolreprod.110.087320

    Article  CAS  PubMed  Google Scholar 

  8. Cheng CY (2014) Toxicants target cell junctions in the testis: insights from the indazole-carboxylic acid model. Spermatogenesis 4(2):e981485. https://doi.org/10.4161/21565562.2014.981485

    Article  PubMed  Google Scholar 

  9. Cheng CY, Mruk DD (2012) The blood-testis barrier and its implications for male contraception. Pharmacol Rev 64(1):16–64. https://doi.org/10.1124/pr.110.002790

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gao Y, Mruk DD, Cheng CY (2015) Sertoli cells are the target of environmental toxicants in the testis - a mechanistic and therapeutic insight. Expert Opin Ther Targets 19(8):1073–1090. https://doi.org/10.1517/14728222.2015.1039513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li N, Mruk DD, Lee WM, Wong CK, Cheng CY (2016) Is toxicant-induced Sertoli cell injury in vitro a useful model to study molecular mechanisms in spermatogenesis? Semin Cell Dev Biol 59:141–156. https://doi.org/10.1016/j.semcdb.2016.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Monsees TK, Franz M, Gebhardt S, Winterstein U, Schill WB, Hayatpour J (2000) Sertoli cells as a target for reproductive hazards. Andrologia 32(4–5):239–246

    Article  CAS  PubMed  Google Scholar 

  13. Wan HT, Mruk DD, Wong CK, Cheng CY (2013) The apical ES-BTB-BM functional axis is an emerging target for toxicant-induced infertility. Trends Mol Med 19(7):396–405. https://doi.org/10.1016/j.molmed.2013.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Boekelheide K, Neely MD, Sioussat TM (1989) The Sertoli cell cytoskeleton: a target for toxicant-induced germ cell loss. Toxicol Appl Pharmacol 101(3):373–389

    Article  CAS  PubMed  Google Scholar 

  15. Johnson KJ (2014) Testicular histopathology associated with disruption of the Sertoli cell cytoskeleton. Spermatogenesis 4(2):e979106. https://doi.org/10.4161/21565562.2014.979106

    Article  PubMed  Google Scholar 

  16. Russell LD, Peterson RN (1985) Sertoli cell junctions: morphological and functional correlates. Int Rev Cytol 94:177–211

    Article  CAS  PubMed  Google Scholar 

  17. Mruk DD, Cheng CY (2015) The mammalian blood-testis barrier: its biology and regulation. Endocr Rev 36(5):564–591. https://doi.org/10.1210/er.2014-1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yan HH, Mruk DD, Lee WM, Cheng CY (2007) Ectoplasmic specialization: a friend or a foe of spermatogenesis? BioEssays 29(1):36–48. https://doi.org/10.1002/bies.20513

    Article  PubMed  PubMed Central  Google Scholar 

  19. O'Donnell L, O'Bryan MK (2014) Microtubules and spermatogenesis. Semin Cell Dev Biol 30:45–54. https://doi.org/10.1016/j.semcdb.2014.01.003

    Article  PubMed  Google Scholar 

  20. Aumuller G, Schulze C, Viebahn C (1992) Intermediate filaments in Sertoli cells. Microsc Res Tech 20(1):50–72. https://doi.org/10.1002/jemt.1070200107

    Article  CAS  PubMed  Google Scholar 

  21. Wen Q et al (2016) Transport of germ cells across the seminiferous epithelium during spermatogenesis-the involvement of both actin- and microtubule-based cytoskeletons. Tissue Barriers 4(4):e1265042. https://doi.org/10.1080/21688370.2016.1265042

    Article  PubMed  PubMed Central  Google Scholar 

  22. Guttman JA, Kimel GH, Vogl AW (2000) Dynein and plus-end microtubule-dependent motors are associated with specialized Sertoli cell junction plaques (ectoplasmic specializations). J Cell Sci 113(Pt 12):2167–2176

    CAS  PubMed  Google Scholar 

  23. Jenardhanan P, Mathur PP (2014) Kinases as targets for chemical modulators: structural aspects and their role in spermatogenesis. Spermatogenesis 4(2):e979113. https://doi.org/10.4161/21565562.2014.979113

    Article  PubMed  Google Scholar 

  24. Wan HT et al (2014) Role of non-receptor protein tyrosine kinases in spermatid transport during spermatogenesis. Semin Cell Dev Biol 30:65–74. https://doi.org/10.1016/j.semcdb.2014.04.013

    Article  CAS  PubMed  Google Scholar 

  25. Chojnacka K, Mruk DD (2015) The Src non-receptor tyrosine kinase paradigm: new insights into mammalian Sertoli cell biology. Mol Cell Endocrinol 415:133–142. https://doi.org/10.1016/j.mce.2015.08.012

    Article  CAS  PubMed  Google Scholar 

  26. Almog T, Naor Z (2008) Mitogen activated protein kinases (MAPKs) as regulators of spermatogenesis and spermatozoa functions. Mol Cell Endocrinol 282(1–2):39–44. https://doi.org/10.1016/j.mce.2007.11.011

    Article  CAS  PubMed  Google Scholar 

  27. Gungor-Ordueri NE, Mruk DD, Wan HT, Wong EW, Celik-Ozenci C, Lie PP, Cheng CY (2014) New insights into FAK function and regulation during spermatogenesis. Histol Histopathol 29(8):977–989. https://doi.org/10.14670/HH-29.977

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Tang EI, Mruk DD, Cheng CY (2013) MAP/microtubule affinity-regulating kinases, microtubule dynamics, and spermatogenesis. J Endocrinol 217(2):R13–R23. https://doi.org/10.1530/JOE-12-0586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schaller MD, Borgman CA, Cobb BS, Vines RR, Reynolds AB, Parsons JT (1992) pp125FAK a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc Natl Acad Sci U S A 89(11):5192–5196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Roskoski R Jr (2004) Src protein-tyrosine kinase structure and regulation. Biochem Biophys Res Commun 324(4):1155–1164. https://doi.org/10.1016/j.bbrc.2004.09.171

    Article  CAS  PubMed  Google Scholar 

  31. Marx A, Nugoor C, Panneerselvam S, Mandelkow E (2010) Structure and function of polarity-inducing kinase family MARK/par-1 within the branch of AMPK/Snf1-related kinases. FASEB J 24(6):1637–1648. https://doi.org/10.1096/fj.09-148064

    Article  CAS  PubMed  Google Scholar 

  32. Cowan-Jacob SW (2006) Structural biology of protein tyrosine kinases. Cell Mol Life Sci 63(22):2608–2625. https://doi.org/10.1007/s00018-006-6202-8

    Article  CAS  PubMed  Google Scholar 

  33. Hubbard SR, Till JH (2000) Protein tyrosine kinase structure and function. Annu Rev Biochem 69:373–398. https://doi.org/10.1146/annurev.biochem.69.1.373

    Article  CAS  PubMed  Google Scholar 

  34. Hall JE, Fu W, Schaller MD (2011) Focal adhesion kinase: exploring Fak structure to gain insight into function. Int Rev Cell Mol Biol 288:185–225. https://doi.org/10.1016/B978-0-12-386041-5.00005-4

    Article  CAS  PubMed  Google Scholar 

  35. Naz F, Anjum F, Islam A, Ahmad F, Hassan MI (2013) Microtubule affinity-regulating kinase 4: structure, function, and regulation. Cell Biochem Biophys 67(2):485–499. https://doi.org/10.1007/s12013-013-9550-7

    Article  CAS  PubMed  Google Scholar 

  36. Tang EI et al (2012) Microtubule affinity-regulating kinase 4 (MARK4) is a component of the ectoplasmic specialization in the rat testis. Spermatogenesis 2(2):117–126. https://doi.org/10.4161/spmg.20724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Corsi JM, Rouer E, Girault JA, Enslen H (2006) Organization and post-transcriptional processing of focal adhesion kinase gene. BMC Genomics 7:198. https://doi.org/10.1186/1471-2164-7-198

    Article  PubMed  PubMed Central  Google Scholar 

  38. Al-Khalili O, Duke BJ, Zeltwanger S, Eaton DC, Spier B, Stockand JD (2001) Cloning of the proto-oncogene c-src from rat testis. DNA Seq 12(5–6):425–429

    Article  CAS  PubMed  Google Scholar 

  39. Kierszenbaum AL, Rivkin E, Talmor-Cohen A, Shalgi R, Tres LL (2009) Expression of full-length and truncated Fyn tyrosine kinase transcripts and encoded proteins during spermatogenesis and localization during acrosome biogenesis and fertilization. Mol Reprod Dev 76(9):832–843. https://doi.org/10.1002/mrd.21049

    Article  CAS  PubMed  Google Scholar 

  40. Bordeleau LJ, Leclerc P (2008) Expression of hck-tr, a truncated form of the src-related tyrosine kinase hck, in bovine spermatozoa and testis. Mol Reprod Dev 75(5):828–837. https://doi.org/10.1002/mrd.20814

    Article  CAS  PubMed  Google Scholar 

  41. Singh AK, Tasken K, Walker W, Frizzell RA, Watkins SC, Bridges RJ, Bradbury NA (1998) Characterization of PKA isoforms and kinase-dependent activation of chloride secretion in T84 cells. Am J Phys 275(2 Pt 1):C562–C570

    Article  CAS  Google Scholar 

  42. Lie PP, Mruk DD, Mok KW, Su L, Lee WM, Cheng CY (2012) Focal adhesion kinase-Tyr407 and -Tyr397 exhibit antagonistic effects on blood-testis barrier dynamics in the rat. Proc Natl Acad Sci U S A 109(31):12562–12567. https://doi.org/10.1073/pnas.1202316109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rovelet-Lecrux A et al (2015) De novo deleterious genetic variations target a biological network centered on Abeta peptide in early-onset Alzheimer disease. Mol Psychiatry 20(9):1046–1056. https://doi.org/10.1038/mp.2015.100

    Article  CAS  PubMed  Google Scholar 

  44. The UniProt C (2017) UniProt: the universal protein knowledgebase. Nucleic Acids Res 45(D1):D158–D169. https://doi.org/10.1093/nar/gkw1099

    Article  Google Scholar 

  45. Finn RD et al (2014) Pfam: the protein families database. Nucleic Acids Res 42(Database issue):D222–D230. https://doi.org/10.1093/nar/gkt1223

    Article  CAS  PubMed  Google Scholar 

  46. Piovesan D et al (2017) DisProt 7.0: a major update of the database of disordered proteins. Nucleic Acids Res 45(D1):D1123–D1124. https://doi.org/10.1093/nar/gkw1279

    Article  CAS  PubMed  Google Scholar 

  47. Buchan DW, Minneci F, Nugent TC, Bryson K, Jones DT (2013) Scalable web services for the PSIPRED protein analysis workbench. Nucleic Acids Res 41(Web Server issue):W349–W357. https://doi.org/10.1093/nar/gkt381

    Article  PubMed  PubMed Central  Google Scholar 

  48. Greene LH et al (2007) The CATH domain structure database: new protocols and classification levels give a more comprehensive resource for exploring evolution. Nucleic Acids Res 35(Database issue):D291–D297. https://doi.org/10.1093/nar/gkl959

    Article  CAS  PubMed  Google Scholar 

  49. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ (1990) Basic local alignment search tool. J Mol Biol 215(3):403–410. https://doi.org/10.1016/S0022-2836(05)80360-2

    Article  CAS  PubMed  Google Scholar 

  50. Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234(3):779–815. https://doi.org/10.1006/jmbi.1993.1626

    Article  CAS  PubMed  Google Scholar 

  51. Berman HM et al (2002) The protein data bank. Acta Crystallogr D Biol Crystallogr 58(Pt 6 No 1):899–907

    Google Scholar 

  52. Boratyn GM, Schaffer AA, Agarwala R, Altschul SF, Lipman DJ, Madden TL (2012) Domain enhanced lookup time accelerated BLAST. Biol Direct 7:12. https://doi.org/10.1186/1745-6150-7-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y (2015) The I-TASSER suite: protein structure and function prediction. Nat Methods 12(1):7–8. https://doi.org/10.1038/nmeth.3213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim DE, Chivian D, Baker D (2004) Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res 32(Web Server issue):W526–W531. https://doi.org/10.1093/nar/gkh468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Corpet F (1988) Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res 16(22):10881–10890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4(3):435–447. https://doi.org/10.1021/ct700301q

    Article  CAS  PubMed  Google Scholar 

  57. Pronk S et al (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29(7):845–854. https://doi.org/10.1093/bioinformatics/btt055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim S et al (2016) PubChem substance and compound databases. Nucleic Acids Res 44(D1):D1202–D1213. https://doi.org/10.1093/nar/gkv951

    Article  CAS  PubMed  Google Scholar 

  59. Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J Med Chem 47(7):1750–1759. https://doi.org/10.1021/jm030644s

    Article  CAS  PubMed  Google Scholar 

  60. Dixon SL, Smondyrev AM, Knoll EH, Rao SN, Shaw DE, Friesner RA (2006) PHASE: a new engine for pharmacophore perception, 3D QSAR model development, and 3D database screening: 1. Methodology and preliminary results. J Comput Aided Mol Des 20(10–11):647–671. https://doi.org/10.1007/s10822-006-9087-6

    Article  CAS  PubMed  Google Scholar 

  61. Schuttelkopf AW, van Aalten DM (2004) PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr 60(Pt 8):1355–1363. https://doi.org/10.1107/S0907444904011679

    Article  PubMed  Google Scholar 

  62. Jenardhanan P, Mannu J, Mathur PP (2014) The structural analysis of MARK4 and the exploration of specific inhibitors for the MARK family: a computational approach to obstruct the role of MARK4 in prostate cancer progression. Mol BioSyst 10(7):1845–1868. https://doi.org/10.1039/c3mb70591a

    Article  CAS  PubMed  Google Scholar 

  63. Halgren TA (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49(2):377–389. https://doi.org/10.1021/ci800324m

    Article  CAS  PubMed  Google Scholar 

  64. Iwatani M et al (2013) Discovery and characterization of novel allosteric FAK inhibitors. Eur J Med Chem 61:49–60. https://doi.org/10.1016/j.ejmech.2012.06.035

    Article  CAS  PubMed  Google Scholar 

  65. Al-Obeidi FA, Lam KS (2000) Development of inhibitors for protein tyrosine kinases. Oncogene 19(49):5690–5701. https://doi.org/10.1038/sj.onc.1203926

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Centre for Bioinformatics, Pondicherry University, Puducherry, India

    Pranitha Jenardhanan & Manivel Panneerselvam

  2. Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India

    Premendu P. Mathur

  3. KIIT University, Bhubaneshwar, Odisha, India

    Premendu P. Mathur

Authors
  1. Pranitha Jenardhanan
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  2. Manivel Panneerselvam
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  3. Premendu P. Mathur
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Corresponding author

Correspondence to Premendu P. Mathur .

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Editors and Affiliations

  1. Department of Microscopy, Laboratory of Cell Biology and Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

    Marco G. Alves

  2. Department of Microscopy, Laboratory of Cell Biology and Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

    Pedro F. Oliveira

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Jenardhanan, P., Panneerselvam, M., Mathur, P.P. (2018). Computational Methods Involved in Evaluating the Toxicity of the Reproductive Toxicants in Sertoli Cell. In: Alves, M., Oliveira, P. (eds) Sertoli Cells. Methods in Molecular Biology, vol 1748. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7698-0_18

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  • DOI: https://doi.org/10.1007/978-1-4939-7698-0_18

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