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Detailed molecular dynamics simulations of human transferrin provide insights into iron release dynamics at serum and endosomal pH

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Abstract

Human serum transferrin (hTf) transports ferric ions in the blood stream and delivers them to cells via receptor-mediated endocytosis. hTf is folded into two homologous lobes; we utilize three of the available crystal structures delineating large conformational changes involved in iron binding/dissociation. We address the problems of whether the release process follows the same trend at serum (~7.4) and endosomal (~5.6) pH, and if there is communication between the lobes. In the absence of the transferrin receptor, we study the dynamics of the full structure as well as the separate lobes in different closed, partially open, and open conformations under neutral and endosomal pH conditions. Results corroborate those experimental observations underscoring the distinguishing effect of pH on the dynamics of hTf. Furthermore, in a total of 2 μs molecular dynamics simulations, residue fluctuations elucidate the cross talk between the lobes correlated by the peptide linker bridging them at serum pH, while their correlations are lost under endosomal conditions. At serum pH, interplay between relative mobility of the lobes is correlated with iron release rates, rendering the initial conformational change an important contributor to the dynamics under these conditions. Interestingly, C-lobe opening lags behind that of the N-lobe as long as there is at least one iron bound, making the more stable C-lobe an attractive target for recognition by receptors. At endosomal pH, both lobes readily open, making irons available for delivery.

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Abbreviations

A:

Apo human transferrin

H:

Holo human transferrin

H**:

Holo human transferrin with locked irons

H*:

One tyrosine contacting Fe+3 from each lobe deprotonated (Y188 and Y517)

HFe+N :

Fe+3 only in N-lobe

HFe+C :

Fe+3 only in C-lobe

HN :

N-lobe only; Fe+3 included

HC :

C-lobe only; Fe+3 included

H† :

Holo human transferrin at endosomal pH

hTf:

Human serum transferrin

PO:

Partially open human transferrin

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

Tf:

Transferrin family

TfR:

Transferrin receptor

References

  1. Sheftel AD, Mason AB, Ponka P (2012) Biochimica Et Biophysica Acta General Subjects 1820:161–187

    Article  CAS  Google Scholar 

  2. Andrews NC (2005) Best Pract Res Clin Haematol 18:159–169

    Article  CAS  PubMed  Google Scholar 

  3. Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Cell 142:24–38

    Article  CAS  PubMed  Google Scholar 

  4. Cheng Y, Zak O, Alsen P, Harrison SC, Walz T (2004) Cell 116:565–576

    Article  CAS  PubMed  Google Scholar 

  5. Lambert LA, Perri H, Halbrooks PJ, Mason AB (2005) Comp Biochem Physiol B Biochem Mol Biol 142:129–141

    Article  PubMed  Google Scholar 

  6. Sun H, Li H, Sadler PJ (1999) Chem Rev 99:2817–2842

    Article  CAS  PubMed  Google Scholar 

  7. Aisen P, Enns C, Wessling-Resnick M (2001) Int J Biochem Cell Biol 33:940–959

    Article  CAS  PubMed  Google Scholar 

  8. Wally J, Halbrooks PJ, Vonrhein C, Rould MA, Everse SJ, Mason AB, Buchanan SK (2006) J Biol Chem 281:24934–24944

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Noinaj N, Easley NC, Oke M, Mizuno N, Gumbart J, Boura E, Steere AN, Zak O, Aisen P, Tajkhorshid E, Evans RW, Gorringe AR, Mason AB, Steven AC, Buchanan SK (2012) Nature 483:53–58

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Yang N, Zhang H, Wang M, Hao Q, Sun H (2012) Sci Rep 2:999

    PubMed Central  PubMed  Google Scholar 

  11. Rinaldo D, Field MJ (2003) Biophys J 85:3485–3501

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Steere AN, Byrne SL, Chasteen ND, Mason AB (2012) Biochim Biophys Acta 1820:326–333

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Mujika JI, Escribano B, Akhmatskaya E, Ugalde JM, Lopez X (2012) Biochemistry 51:7017–7027

    Article  CAS  PubMed  Google Scholar 

  14. Dewan JC, Mikami B, Hirose M, Sacchettini JC (1993) Biochemistry 32:11963–11968

    Article  CAS  PubMed  Google Scholar 

  15. Halbrooks PJ, He QY, Briggs SK, Everse SJ, Smith VC, MacGillivray RTA, Mason AB (2003) Biochemistry 42:3701–3707

    Article  CAS  PubMed  Google Scholar 

  16. Mujika JI, Lopez X, Rezabal E, Castillo R, Marti S, Moliner V, Ugalde JM (2011) J Inorg Biochem 105:1446–1456

    Article  CAS  PubMed  Google Scholar 

  17. Negi S, Aykut AO, Atilgan AR, Atilgan C (2012) J Phys Chem B 116:7145–7153

    Article  CAS  PubMed  Google Scholar 

  18. Guven G, Atilgan AR, Atilgan C (2014) J Phys Chem B 118:11677–11687

    Article  CAS  PubMed  Google Scholar 

  19. Aykut AO, Atilgan AR, Atilgan C (2013) PLoS Comput Biol 9:e1003366

    Article  PubMed Central  PubMed  Google Scholar 

  20. Atilgan C, Atilgan AR (2009) PLoS Comput Biol 5:e1000544

    Article  PubMed Central  PubMed  Google Scholar 

  21. Harris WR (2012) Biochim Biophys Acta 1820:348–361

    Article  CAS  PubMed  Google Scholar 

  22. Adams TE, Mason AB, He Q-Y, Halbrooks PJ, Briggs SK, Smith VC, MacGillivray RTA, Everse SJ (2003) J Biol Chem 278:6027–6033

    Article  CAS  PubMed  Google Scholar 

  23. MacGillivray RTA, Moore SA, Chen J, Anderson BF, Baker H, Luo Y, Bewley M, Smith CA, Murphy MEP, Wang Y, Mason AB, Woodworth RC, Brayer GD, Baker EN (1998) Biochemistry 37:7919–7928

    Article  CAS  PubMed  Google Scholar 

  24. Moore SA, Anderson BF, Groom CR, Haridas M, Baker EN (1997) J Mol Biol 274:222–236

    Article  CAS  PubMed  Google Scholar 

  25. Bewley MC, Tam BM, Grewal J, He S, Shewry S, Murphy MEP, Mason AB, Woodworth RC, Baker EN, MacGillivray RTA (1999) Biochemistry 38:2535–2541

    Article  CAS  PubMed  Google Scholar 

  26. Bas DC, Rogers DM, Jensen JH (2008) Proteins Struct Funct Bioinform 73:765–783

    Article  CAS  Google Scholar 

  27. Gordon JC, Myers JB, Folta T, Shoja V, Heath LS, Onufriev A (2005) Nucleic Acids Res 33:W368–W371

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Clarkson J, Smith DA (2001) FEBS Lett 503:30–34

    Article  CAS  PubMed  Google Scholar 

  29. Sun X, Sun H, Ge R, Richter M, Woodworth RC, Mason AB, He Q-Y (2004) FEBS Lett 573:181–185

    Article  CAS  PubMed  Google Scholar 

  30. Kubal G, Sadler PJ, Tucker A (1994) Eur J Biochem 220:781–787

    Article  CAS  PubMed  Google Scholar 

  31. Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, Chipot C, Skeel RD, Kale L, Schulten K (2005) J Comput Chem 26:1781–1802

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Humphrey W, Dalke A, Schulten K (1996) J Mol Graph 14:33–38

    Article  CAS  PubMed  Google Scholar 

  33. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S et al (1983) J Comput Chem 4:187–217

    Article  CAS  Google Scholar 

  34. Raiteri P, Gale JD (2010) J Am Chem Soc 132:17623–17634

    Article  CAS  PubMed  Google Scholar 

  35. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  36. Darden T, Perera L, Li LP, Pedersen L (1999) Struct Fold Des 7:R55–R60

    Article  CAS  Google Scholar 

  37. Andersen HC (1983) J Comput Phys 52:24–34

    Article  CAS  Google Scholar 

  38. Byrne SL, Chasteen ND, Steere AN, Mason AB (2010) J Mol Biol 396:130–140

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Byrne SL, Steere AN, Chasteen ND, Mason AB (2010) Biochemistry 49:4200–4207

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Steere AN, Byrne SL, Chasteen ND, Smith VC, MacGillivray RTA, Mason AB (2010) J Biol Inorg Chem 15:1341–1352

    Article  CAS  PubMed  Google Scholar 

  41. Eckenroth BE, Steere AN, Chasteen ND, Everse SJ, Mason AB (2011) Proc Natl Acad Sci 108:13089–13094

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Hirose M (2000) Biosci. Biotechnol Biochem 64:1328–1336

    Article  CAS  Google Scholar 

  43. Mason AB, He QY, Adams TE, Gumerov DR, Kaltashov IA, Nguyen V, MacGillivray RTA (2001) Protein Expr Purif 23:142–150

    Article  CAS  PubMed  Google Scholar 

  44. He QY, Mason AB, Woodworth RC, Tam BM, MacGillivray RTA, Grady JK, Chasteen ND (1997) Biochemistry 36:14853–14860

    Article  CAS  PubMed  Google Scholar 

  45. Baker HM, He Q-Y, Briggs SK, Mason AB, Baker EN (2003) Biochemistry 42:7084–7089

    Article  CAS  PubMed  Google Scholar 

  46. He Q-Y, Mason AB, Woodworth RC, Tam BM, Wadsworth T, MacGillivray RTA (1997) Biochemistry 36:5522–5528

    Article  CAS  PubMed  Google Scholar 

  47. Bobst CE, Zhang M, Kaltashov IA (2009) J Mol Biol 388:954–967

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Mathies G, Gast P, Chasteen ND, Luck A, Mason A, Groenen EJ (2014) J Biol Inorg Chem (in press)

  49. James NG, Byme SL, Steere AN, Smith VC, MacGillivray RTA, Mason AB (2009) Biochemistry 48:2858–2867

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. He QY, Mason AB, Tam BM, MacGillivray RTA, Woodworth RC (1999) Biochemistry 38:9704–9711

    Article  CAS  PubMed  Google Scholar 

  51. Steinlein LM, Ligman CM, Kessler S, Ikeda RA (1998) Biochemistry 37:13696–13703

    Article  CAS  PubMed  Google Scholar 

  52. Mason AB, Byrne SL, Everse SJ, Roberts SE, Chasteen ND, Smith VC, MacGillivray RTA, Kandemir B, Bou-Abdallah F (2009) J Mol Recognit 22:521–529

    Article  CAS  PubMed  Google Scholar 

  53. Bali PK, Aisen P (1991) Biochemistry 30:9947–9952

    Article  CAS  PubMed  Google Scholar 

  54. Huebers H, Josephson B, Huebers E, Csiba E, Finch C (1981) Proc Natl Acad Sci 78:2572–2576

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Zak O, Aisen P (2003) Biochemistry 42:12330–12334

    Article  CAS  PubMed  Google Scholar 

  56. Dautryvarsat A, Ciechanover A, Lodish HF (1983) Proc Natl Acad Sci 80:2258–2262

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Scientific and Technological Research Council of Turkey Projects (Grant Numbers 110T624 and 113Z408).

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Authors and Affiliations

  1. Faculty of Engineering and Natural Sciences, Sabanci University, Tuzla, 34956, Istanbul, Turkey

    Haleh Abdizadeh, Ali Rana Atilgan & Canan Atilgan

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  1. Haleh Abdizadeh
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  2. Ali Rana Atilgan
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Correspondence to Canan Atilgan.

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Abdizadeh, H., Atilgan, A.R. & Atilgan, C. Detailed molecular dynamics simulations of human transferrin provide insights into iron release dynamics at serum and endosomal pH. J Biol Inorg Chem 20, 705–718 (2015). https://doi.org/10.1007/s00775-015-1256-4

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