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Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity

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Abstract

Metal ions have been shown to play a critical role in β-amyloid (Aβ) neurotoxicity, thus prompting an intense investigation into the formation of metal–Aβ complexes. Isothermal titration calorimetry (ITC) has been widely used to determine binding constants (K) for a variety of metal–protein interactions, including those in metal–Aβ complexes. In this study, ITC was used to more fully quantify the thermodynamics (K, ΔG, ΔH, and TΔS) of Cu2+ binding to Aβ16, N-acetyl-Aβ16, Aβ28, N-acetyl-Aβ28, and Aβ28 variants (H6A, H13A, H14A) at pH 7.4 and 37 °C. After deconvolution of competing reactions, K for Aβ16 was found to be 1.1 (±0.13) × 109 and is in strong agreement with literature values measured under similar conditions. Further, a similar K value was obtained at two additional concentrations of competing ligand, suggesting that ternary complex formation is not significant. The acetylated peptide analogs reveal a marked decrease in the overall free energy upon binding, which is the result of less favorable enthalpic and entropic contributions. Circular dichroism spectroscopy shows conformational changes that are consistent with these results. Most importantly, data for Aβ28 variants lacking a potential Cu2+-binding histidine residue reveal that the overall free energy of binding remains constant, which is the result of entropy/enthalpy compensation. These data provide fundamental thermodynamic evidence for coordination plasticity in Cu2+ binding to Aβ and other intrinsically disordered peptides.

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Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Scheme 2

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Abbreviations

Aβ:

β-Amyloid

ACES:

N-(2-Acetomido)-2-aminoethanesulfonic acid

AD:

Alzheimer’s disease

CD:

Circular dichroism

ITC:

Isothermal titration calorimetry

References

  1. Anonymous (2011) Alzheimers Dement 7:1–63

    Google Scholar 

  2. Hebert L, Scherr P, Bienias J, Bennett D, Evans D (2003) Arch Neurol 60:1119–1122

    Article  PubMed  Google Scholar 

  3. Barnham KJ, Masters CL, Bush AI (2004) Nat Rev Drug Discov 3:205–214

    Article  PubMed  CAS  Google Scholar 

  4. Glenner GG (1981) Ann Pathol 1:105–108

    PubMed  CAS  Google Scholar 

  5. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Proc Natl Acad Sci USA 82:4245–4249

    Article  PubMed  CAS  Google Scholar 

  6. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Mullerhill B (1987) Nature 325:733–736

    Article  PubMed  CAS  Google Scholar 

  7. Beauchemin D, Kisilevsky R (1998) Anal Chem 70:1026

    Article  PubMed  CAS  Google Scholar 

  8. Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) J Neurol Sci 158:47–52

    Article  PubMed  CAS  Google Scholar 

  9. Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G, Carey PR (2003) Biochemistry 42:2768–2773

    Article  PubMed  CAS  Google Scholar 

  10. Tougu V, Tiiman A, Palumaa P (2011) Metallomics 3:250–261

    Article  PubMed  CAS  Google Scholar 

  11. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Neuron 30:665–676

    Article  PubMed  CAS  Google Scholar 

  12. Bush AI, Tanzi RE (2008) Neurotherapeutics 5:421–432

    Article  PubMed  CAS  Google Scholar 

  13. Faller P, Hureau C (2009) Dalton Trans 13:1080–1094

    Google Scholar 

  14. Miura T, Suzuki K, Kohata N, Takeuchi H (2000) Biochemistry 39:7024–7031

    Article  PubMed  CAS  Google Scholar 

  15. Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ (2001) J Biol Chem 276:20466–20473

    Article  PubMed  CAS  Google Scholar 

  16. Kowalik-Jankowska T, Ruta-Dolejsz M, Wisniewska K, Lankiewicz L (2001) J Inorg Biochem 86:535–545

    Article  PubMed  CAS  Google Scholar 

  17. Kowalik-Jankowska T, Ruta M, Wisniewska K, Lankiewicz L (2003) J Inorg Biochem 95:270–282

    Article  PubMed  CAS  Google Scholar 

  18. Syme CD, Nadal RC, Rigby SEJ, Viles JH (2004) J Biol Chem 279:18169–18177

    Article  PubMed  CAS  Google Scholar 

  19. Karr JW, Kaupp LJ, Szalai VA (2004) J Am Chem Soc 126:13534–13538

    Article  PubMed  CAS  Google Scholar 

  20. Karr JW, Akintoye H, Kaupp LJ, Szalai VA (2005) Biochemistry 44:5478–5487

    Article  PubMed  CAS  Google Scholar 

  21. Karr JW, Szalai VA (2007) J Am Chem Soc 129:3796–3797

    Article  PubMed  CAS  Google Scholar 

  22. Karr JW, Szalai VA (2008) Biochemistry 47:5006–5016

    Article  PubMed  CAS  Google Scholar 

  23. Guilloreau L, Damian L, Coppel Y, Mazarguil H, Winterhalter M, Faller P (2006) J Biol Inorg Chem 11:1024–1038

    Article  PubMed  CAS  Google Scholar 

  24. Minicozzi V, Stellato F, Comai M, Serra MD, Potrich C, Meyer-Klaucke W, Morante S (2008) J Biol Chem 283:10784–10792

    Article  PubMed  CAS  Google Scholar 

  25. Dorlet P, Gambarelli S, Faller P, Hureau C (2009) Angew Chem Int Ed 48:9273–9276

    Article  CAS  Google Scholar 

  26. Drew SC, Noble CJ, Masters CL, Hanson GR, Barnham KJ (2009) J Am Chem Soc 131:1195–1207

    Article  PubMed  CAS  Google Scholar 

  27. Drew SC, Masters CL, Barnham KJ (2009) J Am Chem Soc 131:8760–8761

    Article  PubMed  CAS  Google Scholar 

  28. Garzon-Rodriguez W, Yatsimirsky AK, Glabe CG (1999) Bioorg Med Chem Lett 9:2243–2248

    Article  PubMed  CAS  Google Scholar 

  29. Tougu V, Karafin A, Palumaa P (2008) J Neurochem 104:1249–1259

    Article  PubMed  CAS  Google Scholar 

  30. Sarell CJ, Syme CD, Rigby SEJ, Viles JH (2009) Biochemistry 48:4388–4402

    Article  PubMed  CAS  Google Scholar 

  31. Hong L, Bush WD, Hatcher LQ, Simon J (2008) J Phys Chem B 112:604–611

    Article  PubMed  CAS  Google Scholar 

  32. Hatcher LQ, Hong L, Bush WD, Carducci T, Simon JD (2008) J Phys Chem B 112:8160–8164

    Article  PubMed  CAS  Google Scholar 

  33. Hong L, Carducci TM, Bush WD, Dudzik CG, Millhauser GL, Simon JD (2010) J Phys Chem B 114:11261–11271

    Article  PubMed  CAS  Google Scholar 

  34. Rozga M, Kloniecki M, Dadlez M, Bal W (2010) Chem Res Toxicol 23:336–340

    Article  PubMed  CAS  Google Scholar 

  35. Rozga M, Protas AM, Jablonowska A, Dadlez M, Bal W (2009) Chem Commun 11:1374–1376

    Google Scholar 

  36. Rozga M, Bal W (2010) Chem Res Toxicol 23:298–308

    Article  PubMed  CAS  Google Scholar 

  37. Xiao Z, Wedd AG (2010) Nat Prod Rep 27:768–789

    Article  PubMed  CAS  Google Scholar 

  38. Wilcox DE (2008) Inorg Chim Acta 361:857–867

    Article  CAS  Google Scholar 

  39. Grossoehme NE, Spuches AM, Wilcox DE (2010) J Biol Inorg Chem 15:1183–1191

    Article  PubMed  CAS  Google Scholar 

  40. Shen CL, Scott GL, Merchant F, Murphy RM (1993) Biophys J 65:2383–2395

    Article  PubMed  CAS  Google Scholar 

  41. Talmard C, Guilloreau L, Coppel Y, Mazarguil H, Faller P (2007) Chembiochem 8:163–165

    Article  PubMed  CAS  Google Scholar 

  42. Hong L, Simon JD (2011) Metallomics 3:262–266

    Article  PubMed  CAS  Google Scholar 

  43. Liu RT, McAllister C, Lyubchenko Y, Sierks MR (2004) J Neurosci Res 75:162–171

    Article  PubMed  CAS  Google Scholar 

  44. Gill SC, von Hippel PH (1989) Anal Biochem 182:319–326

    Article  PubMed  CAS  Google Scholar 

  45. Martell AE, Smith RM (2004) NIST Standard Reference Database 46. NIST critically selected stability constants of metal complexes, version 8.0. National Institute of Standards and Technology, Gaithersburg

  46. Trapaidze A, Hureau C, Bal W, Winterhalter M, Faller P (2011) J Biol Inorg Chem 17:37–47

    Google Scholar 

  47. Atwood CS, Scarpa RC, Huang XD, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI (2000) J Neurochem 75:1219–1233

    Article  PubMed  CAS  Google Scholar 

  48. Chen W, Liao Y, Yu H, Cheng IH, Chen Y (2011) J Biol Chem 286:9646–9656

    Article  PubMed  CAS  Google Scholar 

  49. Fawcett TG, Bernarducci EE, Kroghjespersen K, Schugar HJ (1980) J Am Chem Soc 102:2598–2604

    Article  CAS  Google Scholar 

  50. Tsangaris JM, Martin RB (1970) J Am Chem Soc 92:4255–4260

    Article  PubMed  CAS  Google Scholar 

  51. Alies B, Eury H, Bijani C, Rechignat L, Faller P, Hureau C (2011) Inorg Chem 50:11192–11201

    Article  PubMed  CAS  Google Scholar 

  52. LeVine H (2002) Arch Biochem Biophys 404:106–115

    Article  PubMed  CAS  Google Scholar 

  53. Yu H, Ren J, Qu X (2008) Chembiochem 9:879–882

    Article  PubMed  CAS  Google Scholar 

  54. Shivers BD, Hilbich C, Multhaup G, Salbaum M, Beyreuther K, Seeburg PH (1988) EMBO J 7:1365–1370

    PubMed  CAS  Google Scholar 

  55. Busciglio J, Yeh J, Yankner BA (1993) J Neurochem 61:1565–1568

    Article  PubMed  CAS  Google Scholar 

  56. Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NME, Romano DM, Hartshorn MA, Tanzi RE, Bush AI (1998) J Biol Chem 273:12817–12826

    Article  PubMed  CAS  Google Scholar 

  57. Johnstone EM, Chaney MO, Norris FH, Pascual R, Little SP (1991) Mol Brain Res 10:299–305

    Article  PubMed  CAS  Google Scholar 

  58. Gaggelli E, Grzonka Z, Kozlowski H, Migliorini C, Molteni E, Valensin D, Valensin G (2008) Chem Commun 3:341–343

    Google Scholar 

  59. Eury H, Bijani C, Faller P, Hureau C (2011) Angew Chem Int Ed 50:901–905

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank William E. Allen, Andrew Sargent, Andrew Morehead, and Colin Burns for their useful comments and advice. We thank Eli G. Hvastkovs for creating Scheme 2. We would also like to thank Nicholas E. Grossoehme and Dean E. Wilcox for advice on figures, extraction of buffer-independent binding constants, and other useful comments. We thank East Carolina University for the start-up funds that made this work possible. This article is dedicated to the memory of Francesa Spuches.

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Authors and Affiliations

  1. Department of Chemistry, East Carolina University, 300 Science and Technology, Greenville, NC, 27858, USA

    Cristina Sacco, Rachel A. Skowronsky, Sunitha Gade & Anne M. Spuches

  2. Department of Physics, East Carolina University, C209 Howell Science Complex, Greenville, NC, 27858, USA

    John M. Kenney

Authors
  1. Cristina Sacco
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  2. Rachel A. Skowronsky
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  5. Anne M. Spuches
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Correspondence to Anne M. Spuches.

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Sacco, C., Skowronsky, R.A., Gade, S. et al. Calorimetric investigation of copper(II) binding to Aβ peptides: thermodynamics of coordination plasticity. J Biol Inorg Chem 17, 531–541 (2012). https://doi.org/10.1007/s00775-012-0874-3

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  • DOI: https://doi.org/10.1007/s00775-012-0874-3

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