JBIC Journal of Biological Inorganic Chemistry

, Volume 18, Issue 2, pp 183–194 | Cite as

Solution structure and dynamics of human S100A14

  • Ivano Bertini
  • Valentina Borsi
  • Linda Cerofolini
  • Soumyasri Das Gupta
  • Marco Fragai
  • Claudio LuchinatEmail author
Original Paper


Human S100A14 is a member of the EF-hand calcium-binding protein family that has only recently been described in terms of its functional and pathological properties. The protein is overexpressed in a variety of tumor cells and it has been shown to trigger receptor for advanced glycation end products (RAGE)-dependent signaling in cell cultures. The solution structure of homodimeric S100A14 in the apo state has been solved at physiological temperature. It is shown that the protein does not bind calcium(II) ions and exhibits a “semi-open” conformation that thus represents the physiological structure of the S100A14. The lack of two ligands in the canonical EF-hand calcium(II)-binding site explains the negligible affinity for calcium(II) in solution, and the exposed cysteines and histidine account for the observed precipitation in the presence of zinc(II) or copper(II) ions.


Nuclear magnetic resonance Binding affinity Protein folding 



We thank Leonardo Gonnelli for light-scattering measurements. This work was supported by MIUR-FIRB contracts RBLA032ZM7, RBRN07BMCT, and RBIP06LSS2, and by the European Commission, contracts Bio-NMR no. 261863, East-NMR no. 228461, STREP–SFMET no. 201640, WeNMR no. 261572, and INSTRUCT.

Supplementary material

775_2012_963_MOESM1_ESM.pdf (258 kb)
Supplementary material 1 (PDF 258 kb)


  1. 1.
    Marenholz I, Lovering RC, Heizmann CW (2006) Biochim Biophys Acta Mol Cell Res 1763:1282–1283CrossRefGoogle Scholar
  2. 2.
    Donato R (1986) Cell Calcium 7:123–145PubMedCrossRefGoogle Scholar
  3. 3.
    Kojetin DJ, Venters RA, Kordys DR, Thompson RJ, Kumar R, Cavanagh J (2006) Nat Struct Mol Biol 13:641–647PubMedCrossRefGoogle Scholar
  4. 4.
    Marenholz I, Heizmann CW, Fritz G (2004) Biochem Biophys Res Commun 322:1111–1122PubMedCrossRefGoogle Scholar
  5. 5.
    Heizmann CW, Fritz G (2004) Handbook on metalloproteins, 1st edn. Dekker, New YorkGoogle Scholar
  6. 6.
    Donato R (2001) Int J Biochem Cell Biol 33:637–668PubMedCrossRefGoogle Scholar
  7. 7.
    Nelson MR, Chazin WJ (1998) Protein Sci 7:270–282PubMedCrossRefGoogle Scholar
  8. 8.
    Bhattacharya S, Large E, Heizmann CW, Hemmings B, Chazin WJ (2003) Biochemistry 42:14416–14426PubMedCrossRefGoogle Scholar
  9. 9.
    Okada M, Tokumitsu H, Kubota Y, Kobayashi R (2002) Biochem Biophys Res Commun 292:1023–1030PubMedCrossRefGoogle Scholar
  10. 10.
    Agamennone M, Cesari L, Lalli D, Turlizzi E, Del Conte R, Turano P, Mangani S, Padova A (2010) ChemMedChem 5:428–435PubMedCrossRefGoogle Scholar
  11. 11.
    Rety S, Sopkova J, Renouard M, Osterloh D, Gerke V, Tabaries S, Russo-Marie F, Lewit-Bentley A (1999) Nat Struct Biol 6:89–95PubMedCrossRefGoogle Scholar
  12. 12.
    Babini E, Bertini I, Borsi V, Calderone V, Hu X, Luchinat C, Parigi G (2011) J Biol Inorg Chem 16:243–256PubMedCrossRefGoogle Scholar
  13. 13.
    Babini E, Bertini I, Capozzi F, Luchinat C, Quattrone A, Turano M (2005) J Proteome Res 4:1961–1971PubMedCrossRefGoogle Scholar
  14. 14.
    Capozzi F, Luchinat C, Micheletti C, Pontiggia F (2007) J Proteome Res 6:4245–4255PubMedCrossRefGoogle Scholar
  15. 15.
    Moroz OV, Burkitt W, Wittkowski H, He W, Ianoul A, Novitskaya V, Xie JJ, Polyakova O, Lednev IK, Shekhtman A, Derrick PJ, Bjoerk P, Foell D, Bronstein IB (2009) BMC Biochem 10(11):1–18Google Scholar
  16. 16.
    Arnesano F, Banci L, Bertini I, Fantoni A, Tenori L, Viezzoli MS (2005) Angew Chem Int Ed 44:6341–6344CrossRefGoogle Scholar
  17. 17.
    Heizmann CW, Cox JA (1998) Biometals 11:383–397PubMedCrossRefGoogle Scholar
  18. 18.
    Pietas A, Schluns K, Marenholz I, Schafer BW, Heizmann CW, Petersen I (2002) Genomics 79:513–522PubMedCrossRefGoogle Scholar
  19. 19.
    Theorell H, Ehrenberg A (1952) Arch Biochem Biophys 41:442–461CrossRefGoogle Scholar
  20. 20.
    Jin Q, Chen H, Luo A, Ding F, Liu Z (2011) PLoS ONE 6:e19375PubMedCrossRefGoogle Scholar
  21. 21.
    Leclerc E, Fritz G, Vetter SW, Heizmann CW (2009) Biochim Biophys Acta 1793:993–1007PubMedCrossRefGoogle Scholar
  22. 22.
    Keller RLJ (2004) The computer aided resonance assignment tutorial. Cantina Verlag, GoldauGoogle Scholar
  23. 23.
    Shen Y, Delaglio F, Cornilescu G, Bax A (2009) J Biomol NMR 44:213–223PubMedCrossRefGoogle Scholar
  24. 24.
    Herrmann T, Guntert P, Wuthrich K (2002) J Mol Biol 319:209–227PubMedCrossRefGoogle Scholar
  25. 25.
    Ponder JW, Case DA (2003) Adv Protein Chem 66:27–85PubMedCrossRefGoogle Scholar
  26. 26.
    Bertini I, Case DA, Ferella L, Giachetti A, Rosato A (2011) Bioinformatics 27:2384–2390PubMedCrossRefGoogle Scholar
  27. 27.
    Bhattacharya A, Tejero R, Montelione GT (2007) Proteins 66:778–795PubMedCrossRefGoogle Scholar
  28. 28.
    Barbato G, Ikura M, Kay LE, Pastor RW, Bax A (1992) Biochemistry 31:5269–5278PubMedCrossRefGoogle Scholar
  29. 29.
    Kay LE, Torchia DA, Bax A (1989) Biochemistry 28:8972–8979PubMedCrossRefGoogle Scholar
  30. 30.
    Peng JW, Wagner G (1994) Methods Enzymol 239:563–596PubMedCrossRefGoogle Scholar
  31. 31.
    Dosset P, Hus JC, Marion D, Blackledge M (2001) J Biomol NMR 20:223–231PubMedCrossRefGoogle Scholar
  32. 32.
    Garcia de la Torre JG, Huertas ML, Carrasco B (2000) J Magn Reson 147:138–146PubMedCrossRefGoogle Scholar
  33. 33.
    Zhou T, Zheng X, Yi D, Zhang Q (2009) Molecular modeling and structure analysis of S100 calcium binding protein A14: molecular modeling and structure analysis of S100A14. In: Proceedings of 2nd international conference on biomedical engineering and informatics, BMEI 2009, Tianjin, China, 17–19 October 2009, pp 1775–1778Google Scholar
  34. 34.
    Inman KG, Baldisseri DM, Miller KE, Weber DJ (2001) Biochemistry 40:3439–3448PubMedCrossRefGoogle Scholar
  35. 35.
    Zhukov I, Ejchart A, Bierzynski A (2008) Biochemistry 47:640–650PubMedCrossRefGoogle Scholar
  36. 36.
    Dutta K, Cox CJ, Basavappa R, Pascal SM (2008) Biochemistry 47:7637–7647PubMedCrossRefGoogle Scholar
  37. 37.
    Bertini I, Dasgupta S, Hu X, Karavelas T, Luchinat C, Parigi G, Yuan J (2009) J Biol Inorg Chem 14:1097–1107PubMedCrossRefGoogle Scholar
  38. 38.
    Bertini I, Fragai M, Luchinat C, Parigi G (2000) Magn Reson Chem 38:543–550CrossRefGoogle Scholar
  39. 39.
    Maler L, Sastry M, Chazin WJ (2002) J Mol Biol 317:279–290PubMedCrossRefGoogle Scholar
  40. 40.
    Malik S, Revington M, Smith SP, Shaw GS (2008) Proteins 73:28–40PubMedCrossRefGoogle Scholar
  41. 41.
    Rustandi RR, Baldisseri DM, Inman KG, Nizner P, Hamilton SM, Landar A, Landar A, Zimmer DB, Weber DJ (2002) Biochemistry 41:788–796PubMedCrossRefGoogle Scholar
  42. 42.
    Otterbein L, Kordowska J, Witte-Hoffmann C, Wang CL, Dominguez R (2002) Structure 10:557–567PubMedCrossRefGoogle Scholar
  43. 43.
    Smith SP, Shaw GS (1998) Structure 6:211–222PubMedCrossRefGoogle Scholar
  44. 44.
    Drohat AC, Baldisseri DM, Rustandi RR, Weber DJ (1998) Biochemistry 37:2729–2740PubMedCrossRefGoogle Scholar
  45. 45.
    Imai FL, Nagata K, Yonezawa N, Nakano M, Tanokura M (2008) Acta Crystallogr Sect F Struct Biol Cryst Commun 64:70–76PubMedCrossRefGoogle Scholar
  46. 46.
    Zhou Y, Yang W, Kirberger M, Lee HW, Ayalasomayajula G, Yang JJ (2006) Proteins 65:643–655PubMedCrossRefGoogle Scholar
  47. 47.
    Vogel HJ, Brokx RD, Ouyang H (2002) In: Vogel HJ (ed) Calcium-binding protein protocols: volume 1: reviews and case studies. Springer, New YorkGoogle Scholar
  48. 48.
    Houdusse A, Cohen C (1996) Structure 4:21–32PubMedCrossRefGoogle Scholar
  49. 49.
    Santamaria-Kisiel L, Rintala-Dempsey AC, Shaw GS (2006) Biochem J 396:201–214PubMedCrossRefGoogle Scholar
  50. 50.
    Rustandi RR, Baldisseri DM, Weber DJ (2000) Nat Struct Biol 7:570–574PubMedCrossRefGoogle Scholar
  51. 51.
    Rother K, Hildebrand PW, Goede A, Gruening B, Preissner R (2009) Nucleic Acids Res 37:D393–D395PubMedCrossRefGoogle Scholar
  52. 52.
    Wright NT, Varney KM, Ellis KC, Markowitz J, Gitti RK, Zimmer DB, Weber DJ (2005) J Mol Biol 353:410–426PubMedCrossRefGoogle Scholar
  53. 53.
    Koch M, Bhattacharya S, Kehl T, Gimona M, Vasak M, Chazin W, Heimann CW, Kroneck PMH, Fritz G (2007) Biochim Biophys Acta Mole Cell Res 1773:457–470CrossRefGoogle Scholar
  54. 54.
    Fritz G, Mittl PRE, Vasak M, Grutter MG, Heizmann CW (2002) J Biol Chem 277:33092–33098PubMedCrossRefGoogle Scholar
  55. 55.
    Garrett SC, Hodgson L, Rybin A, Toutchkine A, Hahn KM, Lawrence DS, Bresnick AR (2008) Biochemistry 47:986–996PubMedCrossRefGoogle Scholar
  56. 56.
    Schafer BW, Fritschy JM, Murmann P, Troxler H, Durussel I, Heizmann CW, Cox JA (2000) J Biol Chem 275:30623–30630PubMedCrossRefGoogle Scholar
  57. 57.
    Kordowska J, Stafford WF, Wang CLA (1998) Eur J Biochem 253:57–66PubMedCrossRefGoogle Scholar
  58. 58.
    Allen BG, Durussel I, Walsh MP, Cox JA (1996) Biochem Cell Biol 74:687–694PubMedCrossRefGoogle Scholar
  59. 59.
    Sivaraja V, Kumar TKS, Rajalingam D, Graziani I, Prudovsky I, Yu C (2006) Biophys J 91:1832–1843PubMedCrossRefGoogle Scholar
  60. 60.
    Zimmer DB, Weber DJ (2010) Cardiovasc Psychiatry Neurol 2010:1–17Google Scholar
  61. 61.
    Becker T, Gerke V, Kube E, Weber K (1992) Eur J Biochem 207:541–547PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2012

Authors and Affiliations

  • Ivano Bertini
    • 1
    • 2
  • Valentina Borsi
    • 1
  • Linda Cerofolini
    • 1
  • Soumyasri Das Gupta
    • 1
  • Marco Fragai
    • 1
    • 2
  • Claudio Luchinat
    • 1
    • 2
    Email author
  1. 1.Magnetic Resonance Center (CERM)University of FlorenceSesto FiorentinoItaly
  2. 2.Department of ChemistryUniversity of FlorenceSesto FiorentinoItaly

Personalised recommendations