Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-29T18:18:04.903Z Has data issue: false hasContentIssue false
  • English
  • Français

In Silico Investigation of pH-Dependence of Prolactin and Human Growth Hormone Binding to Human Prolactin Receptor

Published online by Cambridge University Press:  03 June 2015

Lin Wang ,
Shawn Witham ,
Zhe Zhang ,
Lin Li ,
Michael Hodsdon  and
Emil Alexov
Lin Wang*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Shawn Witham*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Zhe Zhang*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Lin Li*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
Michael Hodsdon*
Affiliation:
Department of Laboratory Medicine and the Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA
Emil Alexov*
Affiliation:
Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA
*
Email:[email protected]
Email:[email protected]
Email:[email protected]
Email:[email protected]
Email:[email protected]
Corresponding author.Email:[email protected]
Get access

Abstract

Experimental data shows that the binding of human prolactin (hPRL) to human prolactin receptor (hPRLr-ECD) is strongly pH-dependent, while the binding of the same receptor to human growth hormone (hGH) is pH-independent. Here we carry in silico analysis of the molecular effects causing such a difference and reveal the role of individual amino acids. It is shown that the computational modeling correctly predicts experimentally determined pKa’s of histidine residues in an unbound state in the majority of the cases and the pH-dependence of the binding free energy. Structural analysis carried in conjunction with calculated pH-dependence of the binding revealed that the main reason for pH-dependence of the binding of hPRL-hPRLr-ECD is a number of salt-bridges across the interface of the complex, while no salt-bridges are formed in the hGH-hPRlr-ECD. Specifically, most of the salt-bridges involve histidine residues and this is the reason for the pH-dependence across a physiological range of pH. The analysis not only revealed the molecular mechanism of the pH-dependence of the hPRL-hPRLr-ECD, but also provided critical insight into the underlying physic-chemical mechanism.

Keywords

82.20.WtHuman prolactinhuman prolactin receptorhuman growth hormonepKa calculationspH-dependenceelectrostatics
Type
Research Article
Information
Communications in Computational Physics , Volume 13 , Issue 1 , January 2013 , pp. 207 - 222
Copyright
Copyright © Global Science Press Limited 2013

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

[1]Alexov, E., Protein-protein interactions. Curr Pharm Biotechnol, 2008. 9(2): p. 55–6.Google Scholar
[2]Zhang, Z., Witham, S., and Alexov, E., On the role of electrostatics in protein-protein interactions. Phys Biol, 2011. 8(3): p. 035001.Google Scholar
[3]Alexov, E., Calculating proton uptake/release and binding free energy taking into account ionization and conformation changes induced by protein-inhibitor association: application to plasmepsin, cathepsin D and endothiapepsin-pepstatin complexes. Proteins, 2004. 56(3): p. 572–84.CrossRefGoogle ScholarPubMed
[4]Bevilacqua, P.C., Brown, T.S., Chadalavada, D., Lecomte, J., Moody, E., and Nakano, S.I., Linkage between proton binding and folding in RNA: implications for RNA catalysis. Biochem Soc Trans, 2005. 33(Pt 3): p. 466–70.Google Scholar
[5]Matthew, J.B., Gurd, F.R., Garcia-Moreno, B., Flanagan, M.A., March, K.L., and Shire, S.J., pH-dependent processes in proteins. CRC Crit Rev Biochem, 1985. 18(2): p. 91–197.Google Scholar
[6]Talley, K. and Alexov, E., On the pH-optimum of activity and stability of proteins. Proteins, 2010. 78(12): p. 2699–706.Google Scholar
[7]Mitra, R.C., Zhang, Z., and Alexov, E., In silico modeling of pH-optimum of protein-protein binding. Proteins, 2011. 79(3): p. 925–36.CrossRefGoogle ScholarPubMed
[8]Kundrotas, P.J. and Alexov, E., Electrostatic properties of protein-protein complexes. Biophys J, 2006. 91(5): p. 1724–36.Google Scholar
[9]Garcia-Moreno, B., Adaptations of proteins to cellular and subcellular pH. J Biol, 2009. 8(11): p. 98.Google Scholar
[10]Blundell, C.D., Mahoney, D.J., Cordell, M.R., Almond, A., Kahmann, J.D., Perczel, A., Taylor, J.D., Campbell, I.D., and Day, A.J., Determining the molecular basis for the pH-dependent interaction between the link module of human TSG-6 and hyaluronan. J Biol Chem, 2007. 282(17): p. 12976.CrossRefGoogle ScholarPubMed
[11]MacKnight, M.L., Gillard, J.M., and Tollin, G., Flavine-protein interactions in flavoenzymes. The pH dependence of the binding of flavine mononucleotide and riboflavine to Azotobacter flavodoxin. Biochemistry, 1973. 12(21): p. 4200–4206.Google Scholar
[12]Gramberg, T., Soilleux, E., Fisch, T., Lalor, P.F., Hofmann, H., Wheeldon, S., Cotterill, A., Wegele, A., Winkler, T., and Adams, D.H., Interactions of LSECtin and DC-SIGN/DC-SIGNR with viral ligands: Differential pH dependence, internalization and virion binding. Virology, 2008. 373(1): p. 189–201.Google Scholar
[13]Bauman, A.T., Jaron, S., Yukl, E.T., Burchfiel, J.R., and Blackburn, N.J., pH dependence of peptidylglycine monooxygenase. Mechanistic implications of Cu-methionine binding dynamics. Biochemistry, 2006. 45(37): p. 11140–11150.Google Scholar
[14]Sprague, E.R., Martin, W.L., and Bjorkman, PJ., pH dependence and stoichiometry of binding to the Fc region of IgG by the herpes simplex virus Fc receptor gE-gI. J Biol Chem, 2004. 279(14): p. 14184.CrossRefGoogle Scholar
[15]Bidwai, A.K., Ok, E.Y., and Erman, J.E., pH dependence of cyanide binding to the ferric heme domain of the direct oxygen sensor from escherichia coli and the effect of alkaline denaturation. Biochemistry, 2008. 47(39): p. 10458–10470.Google Scholar
[16]Invernizzi, G., Šamalikova, M., Brocca, S., Lotti, M., Molinari, H., and Grandori, R., Comparison of bovine and porcine lactoglobulin: a mass spectrometric analysis. J Mass Spectrometry, 2006. 41(6): p. 717–727.Google Scholar
[17]Fallon, J.L. and Quiocho, F.A., A closed compact structure of native Ca2+-calmodulin. Structure, 2003. 11(10): p. 1303–1307.Google Scholar
[18]Slaughter, B.D., Unruh, J.R., Allen, M.W., Urbauer, R.J.B., and Johnson, C.K., Conformational substates of calmodulin revealed by single-pair fluorescence resonance energy transfer: Influence of solution conditions and oxidative modification. Biochemistry, 2005. 44(10): p. 3694–3707.Google Scholar
[19]Isvoran, A., Craescu, C., and Alexov, E., Electrostatic control of the overall shape of calmodulin: numerical calculations. European Biophys J, 2007. 36(3): p. 225–237.Google Scholar
[20]Konvalinka, J., Horejsi, M., Andreansky, M., Novek, P., Pichova, I., Blaha, I., Fabry, M., Sedlacek, J., Foundling, S., and Strop, P., An engineered retroviral proteinase from myeloblastosis associated virus acquires pH dependence and substrate specificity of the HIV-1 proteinase. EMBO J, 1992. 11(3): p. 1141.Google Scholar
[21]Tynan Connolly, B.M. and Nielsen, J.E., Redesigning protein pKa values. Protein Science, 2007. 16(2): p. 239–249.CrossRefGoogle ScholarPubMed
[22]Labrou, N.E., Rigden, D.J., and Clonis, Y.D., Engineering the pH-dependence of kinetic parameters of maize glutathione S-transferase I by site-directed mutagenesis. Biomolecular Engineering, 2004. 21(2): p. 61–66.CrossRefGoogle ScholarPubMed
[23]Kusano, M., Yasukawa, K., Hashida, Y., and Inouye, K., Engineering of the pH-dependence of thermolysin activity as examined by site-directed mutagenesis of Asn112 located at the active site of thermolysin. J Biochem, 2006. 139(6): p. 1017.Google Scholar
[24]Neves-Petersen, M.T., Petersen, E.I., Fojan, P., Noronha, M., Madsen, R.G., and Petersen, S.B., Engineering the pH-optimum of a triglyceride lipase: from predictions based on electrostatic computations to experimental results. J Biotechnol, 2001. 87(3): p. 225–254.Google Scholar
[25]Liu, B., Westhead, D.R., Boyett, M.R., and Warwicker, J., Modelling the pH-dependent properties of Kv1 potassium channels. J Mol Biol, 2007. 368(2): p. 328–335.CrossRefGoogle ScholarPubMed
[26]Kouranov, A., Xie, L., De La Cruz, J., Chen, L., Westbrook, J., Bourne, P.E., and Berman, H.M., The RCSB PDB information portal for structural genomics. Nucleic Acids Rresearch, 2006. 34(suppl 1): p. D302.Google Scholar
[27]Jensen, J.H., Calculating pH and salt dependence of protein-protein binding. Curr Pharm Biotechnol, 2008. 9(2): p. 96–102.Google Scholar
[28]Talley, K., Ng, C., Shoppell, M., Kundrotas, P., and Alexov, E., On the electrostatic component of protein-protein binding free energy. PMC Biophys, 2008. 1(1): p. 2.Google Scholar
[29]Gibas, C.J., Jambeck, P., and Subramaniam, S., Continuum electrostatic methods applied to pH-dependent properties of antibody-antigen association. Methods, 2000. 20(3): p. 292–309.Google Scholar
[30]Aguilar, B., Anandakrishnan, R., Ruscio, J.Z., and Onufriev, A.V., Statistics and physical origins of pK and ionization state changes upon protein-ligand binding. Biophys J, 2010. 98(5): p. 872–80.Google Scholar
[31]Warwicker, J., Simplified methods for pKa and acid pH-dependent stability estimation in proteins: removing dielectric and counterion boundaries. Protein Science, 1999. 8(02): p. 418–425.Google Scholar
[32]Kulkarni, M.V., Tettamanzi, M.C., Murphy, J.W., Keeler, C., Myszka, D.G., Chayen, N.E., Lolis, E.J., and Hodsdon, M.E., Two independent histidines, one in human prolactin and one in its receptor, are critical for pH-dependent receptor recognition and activation. J Biol Chem, 2010. 285(49): p. 38524–33.Google Scholar
[33]Keeler, C., Jablonski, E.M., Albert, Y.B., Taylor, B.D., Myszka, D.G., Clevenger, C.V., and Hodsdon, M.E., The kinetics of binding human prolactin, but not growth hormone, to the prolactin receptor vary over a physiologic pH range. Biochemistry, 2007. 46(9): p. 2398–410.CrossRefGoogle ScholarPubMed
[34]Somers, W., Ultsch, M., De Vos, A.M., and Kossiakoff, A.A., The X-ray structure of a growth hormone-prolactin receptor complex. Nature, 1994. 372(6505): p. 478–81.Google Scholar
[35]Xiang, J.Z. and Honig, B., Jackal: A protein structure modeling package. Columbia University and Howard Hughes Medical Institute, New York, 2002.Google Scholar
[36]Alexov, E.G. and Gunner, M.R., Incorporating protein conformational flexibility into the calculation of pH-dependent protein properties. Biophys J, 1997. 72(5): p. 2075–93.Google Scholar
[37]Alexov, E.G. and Gunner, M.R., Calculated protein and proton motions coupled to electron transfer: electron transfer from QA-to QB in bacterial photosynthetic reaction centers. Bio-chemistry, 1999. 38(26): p. 8253–70.Google Scholar
[38]Georgescu, R.E., Alexov, E.G., and Gunner, M.R., Combining conformational flexibility and continuum electrostatics for calculating pK(a)s in proteins. Biophys J, 2002. 83(4): p. 1731–48.Google Scholar
[39]Petrey, D. and Honig, B., GRASP2: visualization, surface properties, and electrostatics of macromolecular structures and sequences. Methods Enzymology, 2003. 374: p. 492–509.Google Scholar
[40]Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E., UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem, 2004. 25(13): p. 1605–1612.Google Scholar
[41]Gunner, M.R., Zhu, X., and Klein, M.C., MCCE analysis of the pK(a) s of introduced buried acids and bases in staphylococcal nuclease. Proteins, 2011.Google Scholar
[42]Tettamanzi, M.C., Keeler, C., Meshack, S., and Hodsdon, M.E., Analysis of site-specific histidine protonation in human prolactin. Biochemistry, 2008. 47(33): p. 8638–47.Google Scholar
[43]Xiang, Z. and Honig, B., Extending the accuracy limits of prediction for side-chain conformations. J Mol Biol, 2001. 311(2): p. 421–30.Google Scholar