Skip to main content

A strong 13C chemical shift signature provides the coordination mode of histidines in zinc-binding proteins

Abstract

Zinc is the second most abundant metal ion incorporated in proteins, and is in many cases a crucial component of protein three-dimensional structures. Zinc ions are frequently coordinated by cysteine and histidine residues. Whereas cysteines bind to zinc via their unique Sγ atom, histidines can coordinate zinc with two different coordination modes, either Nδ1 or Nε2 is coordinating the zinc ion. The determination of this coordination mode is crucial for the accurate structure determination of a histidine-containing zinc-binding site by NMR. NMR chemical shifts contain a vast amount of information on local electronic and structural environments and surprisingly their utilization for the determination of the coordination mode of zinc-ligated histidines has been limited so far to 15N nuclei. In the present report, we observed that the 13C chemical shifts of aromatic carbons in zinc-ligated histidines represent a reliable signature of their coordination mode. Using a statistical analysis of 13C chemical shifts, we show that 13Cδ2 chemical shift is sensitive to the histidine coordination mode and that the chemical shift difference δ{13Cε1} − δ{13Cδ2} provides a reference-independent marker of this coordination mode. The present approach allows the direct determination of the coordination mode of zinc-ligated histidines even with non-isotopically enriched protein samples and without any prior structural information.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Andreeva A, Murzin AG (2008) A fortuitous insight into a common mode of RNA recognition by the dsRNA-specific zinc fingers. Proc Natl Acad Sci USA 105(52):E128–E129

    ADS  Article  Google Scholar 

  2. Andreini C, Banci L, Bertini I, Rosato A (2006a) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5(1):196–201

    Article  Google Scholar 

  3. Andreini C, Banci L, Bertini I, Rosato A (2006b) Zinc through the three domains of life. J Proteome Res 5(11):3173–3178

    Article  Google Scholar 

  4. Auld DS (2001) Zinc coordination sphere in biochemical zinc sites. Biometals 14(3–4):271–313

    Article  Google Scholar 

  5. Barraud P, Emmerth S, Shimada Y, Hotz H-R, Allain FH-T, Bühler M (2011) An extended dsRBD with a novel zinc-binding motif mediates nuclear retention of fission yeast Dicer. EMBO J 30(20):4223–4235

    Article  Google Scholar 

  6. Bazzi A, Zargarian L, Chaminade F, Boudier C, De Rocquigny H, Rene B, Mely Y, Fosse P, Mauffret O (2011) Structural insights into the cTAR DNA recognition by the HIV-1 nucleocapsid protein: role of sugar deoxyriboses in the binding polarity of NC. Nucleic Acids Res 39(9):3903–3916

    Article  Google Scholar 

  7. Bessière D, Lacroix C, Campagne S, Ecochard V, Guillet V, Mourey L, Lopez F, Czaplicki J, Demange P, Milon A, Girard J-P, Gervais V (2008) Structure-function analysis of the THAP zinc finger of THAP1, a large C2CH DNA-binding module linked to Rb/E2F pathways. J Biol Chem 283(7):4352–4363

    Article  Google Scholar 

  8. Bourbigot S, Ramalanjaona N, Boudier C, Salgado GF, Roques BP, Mely Y, Bouaziz S, Morellet N (2008) How the HIV-1 nucleocapsid protein binds and destabilises the (−) primer binding site during reverse transcription. J Mol Biol 383(5):1112–1128

    Article  Google Scholar 

  9. Briknarová K, Thomas CJ, York J, Nunberg JH (2011) Structure of a zinc-binding domain in the Junin virus envelope glycoprotein. J Biol Chem 286(2):1528–1536

    Article  Google Scholar 

  10. Cavalli A, Salvatella X, Dobson CM, Vendruscolo M (2007) Protein structure determination from NMR chemical shifts. Proc Natl Acad Sci USA 104(23):9615–9620

    ADS  Article  Google Scholar 

  11. Chakrabarti P (1990) Geometry of interaction of metal ions with histidine residues in protein structures. Protein Eng 4(1):57–63

    Article  Google Scholar 

  12. Cordier F, Vinolo E, Véron M, Delepierre M, Agou F (2008) Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation. J Mol Biol 377(5):1419–1432

    Article  Google Scholar 

  13. Cornilescu G, Delaglio F, Bax A (1999) Protein backbone angle restraints from searching a database for chemical shift and sequence homology. J Biomol NMR 13(3):289–302

    Article  Google Scholar 

  14. Day RM, Thalhauser CJ, Sudmeier JL, Vincent MP, Torchilin EV, Sanford DG, Bachovchin CW, Bachovchin WW (2003) Tautomerism, acid-base equilibria, and H-bonding of the six histidines in subtilisin BPN’ by NMR. Protein Sci 12(4):794–810

    Article  Google Scholar 

  15. De Guzman RN, Liu HY, Martinez-Yamout M, Dyson HJ, Wright PE (2000) Solution structure of the TAZ2 (CH3) domain of the transcriptional adaptor protein CBP. J Mol Biol 303(2):243–253

    Article  Google Scholar 

  16. Dempsey BR, Wrona M, Moulin JM, Gloor GB, Jalilehvand F, Lajoie G, Shaw GS, Shilton BH (2004) Solution NMR structure and X-ray absorption analysis of the C-terminal zinc-binding domain of the SecA ATPase. Biochemistry 43(29):9361–9371

    Article  Google Scholar 

  17. Dupont CL, Butcher A, Valas RE, Bourne PE, Caetano-Anollés G (2010) History of biological metal utilization inferred through phylogenomic analysis of protein structures. Proc Natl Acad Sci USA 107(23):10567–10572

    ADS  Article  Google Scholar 

  18. Estrada DF, Boudreaux DM, Zhong D, St Jeor SC, De Guzman RN (2009) The Hantavirus glycoprotein G1 tail contains dual CCHC-type classical zinc fingers. J Biol Chem 284(13):8654–8660

    Article  Google Scholar 

  19. Eustermann S, Brockmann C, Mehrotra PV, Yang J-C, Loakes D, West SC, Ahel I, Neuhaus D (2010) Solution structures of the two PBZ domains from human APLF and their interaction with poly(ADP-ribose). Nat Struct Mol Biol 17(2):241–243

    Article  Google Scholar 

  20. Eustermann S, Videler H, Yang J-C, Cole PT, Gruszka D, Veprintsev D, Neuhaus D (2011) The DNA-binding domain of human PARP-1 interacts with DNA single-strand breaks as a monomer through its second zinc finger. J Mol Biol 407(1):149–170

    Article  Google Scholar 

  21. Grzesiek S, Bax A (1993) Amino acid type determination in the sequential assignment procedure of uniformly 13C/15 N-enriched proteins. J Biomol NMR 3(2):185–204

    Article  Google Scholar 

  22. Hansen DF, Kay LE (2011) Determining valine side-chain rotamer conformations in proteins from methyl 13C chemical shifts: application to the 360 kDa half-proteasome. J Am Chem Soc 133(21):8272–8281

    Article  Google Scholar 

  23. Hansen DF, Neudecker P, Vallurupalli P, Mulder FAA, Kay LE (2010) Determination of Leu side-chain conformations in excited protein states by NMR relaxation dispersion. J Am Chem Soc 132(1):42–43

    Article  Google Scholar 

  24. Hayes PL, Lytle BL, Volkman BF, Peterson FC (2008) The solution structure of ZNF593 from Homo sapiens reveals a zinc finger in a predominantly unstructured protein. Protein Sci 17(3):571–576

    Article  Google Scholar 

  25. Huang A, de Jong RN, Wienk H, Winkler GS, Timmers HTM, Boelens R (2009) E2-c-Cbl recognition is necessary but not sufficient for ubiquitination activity. J Mol Biol 385(2):507–519

    Article  Google Scholar 

  26. Isernia C, Bucci E, Leone M, Zaccaro L, Di Lello P, Digilio G, Esposito S, Saviano M, Di Blasio B, Pedone C, Pedone PV, Fattorusso R (2003) NMR structure of the single QALGGH zinc finger domain from the Arabidopsis thaliana SUPERMAN protein. ChemBioChem 4(2–3):171–180

    Article  Google Scholar 

  27. King G, Wright PE (1982) A two-dimensional NMR method for assignment of imidazole ring proton resonances of histidine residues in proteins. Biochem Biophys Res Commun 106(2):559–565

    Article  Google Scholar 

  28. Kornhaber GJ, Snyder D, Moseley HNB, Montelione GT (2006) Identification of zinc-ligated cysteine residues based on 13Calpha and 13Cbeta chemical shift data. J Biomol NMR 34(4):259–269

    Article  Google Scholar 

  29. Kostic M, Matt T, Martinez-Yamout MA, Dyson HJ, Wright PE (2006) Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53. J Mol Biol 363(2):433–450

    Article  Google Scholar 

  30. Kwon K, Cao C, Stivers JT (2003) A novel zinc snap motif conveys structural stability to 3-methyladenine DNA glycosylase I. J Biol Chem 278(21):19442–19446

    Article  Google Scholar 

  31. Lee MS, Gippert GP, Soman KV, Case DA, Wright PE (1989) Three-dimensional solution structure of a single zinc finger DNA-binding domain. Science 245(4918):635–637

    ADS  Article  Google Scholar 

  32. Legge GB, Martinez-Yamout MA, Hambly DM, Trinh T, Lee BM, Dyson HJ, Wright PE (2004) ZZ domain of CBP: an unusual zinc finger fold in a protein interaction module. J Mol Biol 343(4):1081–1093

    Article  Google Scholar 

  33. Liew CK, Crossley M, Mackay JP, Nicholas HR (2007) Solution structure of the THAP domain from Caenorhabditis elegans C-terminal binding protein (CtBP). J Mol Biol 366(2):382–390

    Article  Google Scholar 

  34. London RE, Wingad BD, Mueller GA (2008) Dependence of amino acid side chain 13C shifts on dihedral angle: application to conformational analysis. J Am Chem Soc 130(33):11097–11105

    Article  Google Scholar 

  35. Malgieri G, Russo L, Esposito S, Baglivo I, Zaccaro L, Pedone EM, Di Blasio B, Isernia C, Pedone PV, Fattorusso R (2007) The prokaryotic Cys2His2 zinc-finger adopts a novel fold as revealed by the NMR structure of Agrobacterium tumefaciens Ros DNA-binding domain. Proc Natl Acad Sci USA 104(44):17341–17346

    ADS  Article  Google Scholar 

  36. Malgieri G, Zaccaro L, Leone M, Bucci E, Esposito S, Baglivo I, Del Gatto A, Russo L, Scandurra R, Pedone PV, Fattorusso R, Isernia C (2011) Zinc to cadmium replacement in the A. thaliana SUPERMAN Cys His zinc finger induces structural rearrangements of typical DNA base determinant positions. Biopolymers 95(11):801–810

    Google Scholar 

  37. Matsui T, Kodera Y, Endoh H, Miyauchi E, Komatsu H, Sato K, Tanaka T, Kohno T, Maeda T (2007) RNA recognition mechanism of the minimal active domain of the human immunodeficiency virus type-2 nucleocapsid protein. J Biochem 141(2):269–277

    Article  Google Scholar 

  38. Miura S, Ichikawa Y (1991) Proton nuclear magnetic resonance investigation of adrenodoxin. Assignment of aromatic resonances and evidence for a conformational similarity with ferredoxin from Spirulina platensis. Eur J Biochem 197(3):747–757

    Article  Google Scholar 

  39. Möller HM, Martinez-Yamout MA, Dyson HJ, Wright PE (2005) Solution structure of the N-terminal zinc fingers of the Xenopus laevis double-stranded RNA-binding protein ZFa. J Mol Biol 351(4):718–730

    Article  Google Scholar 

  40. Oh BH, Westler WM, Darba P, Markley JL (1988) Protein carbon-13 spin systems by a single two-dimensional nuclear magnetic resonance experiment. Science 240(4854):908–911

    ADS  Article  Google Scholar 

  41. Omichinski JG, Clore GM, Appella E, Sakaguchi K, Gronenborn AM (1990) High-resolution three-dimensional structure of a single zinc finger from a human enhancer binding protein in solution. Biochemistry 29(40):9324–9334

    Article  Google Scholar 

  42. Pelton JG, Torchia DA, Meadow ND, Roseman S (1993) Tautomeric states of the active-site histidines of phosphorylated and unphosphorylated IIIGlc, a signal-transducing protein from Escherichia coli, using two-dimensional heteronuclear NMR techniques. Protein Sci 2(4):543–558

    Article  Google Scholar 

  43. Peroza EA, Schmucki R, Güntert P, Freisinger E, Zerbe O (2009) The beta(E)-domain of wheat E(c)-1 metallothionein: a metal-binding domain with a distinctive structure. J Mol Biol 387(1):207–218

    Article  Google Scholar 

  44. Ramelot TA, Cort JR, Goldsmith-Fischman S, Kornhaber GJ, Xiao R, Shastry R, Acton TB, Honig B, Montelione GT, Kennedy MA (2004) Solution NMR structure of the iron-sulfur cluster assembly protein U (IscU) with zinc bound at the active site. J Mol Biol 344(2):567–583

    Article  Google Scholar 

  45. Reynolds WF, Peat IR, Freedman MH, Lyerla JR (1973) Determination of the tautomeric form of the imidazole ring of l-histidine in basic solution by carbon-13 magnetic resonance spectroscopy. J Am Chem Soc 95(2):328–331

    Article  Google Scholar 

  46. Rosenzweig AC (2002) Metallochaperones: bind and deliver. Chem Biol 9(6):673–677

    Article  Google Scholar 

  47. Schubert M, Labudde D, Oschkinat H, Schmieder P (2002) A software tool for the prediction of Xaa-Pro peptide bond conformations in proteins based on 13C chemical shift statistics. J Biomol NMR 24(2):149–154

    Article  Google Scholar 

  48. Schubert M, Poon DK, Wicki J, Tarling CA, Kwan EM, Nielsen JE, Withers SG, McIntosh LP (2007) Probing electrostatic interactions along the reaction pathway of a glycoside hydrolase: histidine characterization by NMR spectroscopy. Biochemistry 46(25):7383–7395

    Article  Google Scholar 

  49. Sharma D, Rajarathnam K (2000) 13C NMR chemical shifts can predict disulfide bond formation. J Biomol NMR 18(2):165–171

    Article  Google Scholar 

  50. Sharpe BK, Matthews JM, Kwan AH, Newton A, Gell DA, Crossley M, Mackay JP (2002) A new zinc binding fold underlines the versatility of zinc binding modules in protein evolution. Structure 10(5):639–648

    Article  Google Scholar 

  51. Sharpe BK, Liew CK, Kwan AH, Wilce JA, Crossley M, Matthews JM, Mackay JP (2005) Assessment of the robustness of a serendipitous zinc binding fold: mutagenesis and protein grafting. Structure 13(2):257–266

    Article  Google Scholar 

  52. Shen Y, Lange O, Delaglio F, Rossi P, Aramini JM, Liu G, Eletsky A, Wu Y, Singarapu KK, Lemak A, Ignatchenko A, Arrowsmith CH, Szyperski T, Montelione GT, Baker D, Bax A (2008) Consistent blind protein structure generation from NMR chemical shift data. Proc Natl Acad Sci USA 105(12):4685–4690

    ADS  Article  Google Scholar 

  53. Shen Y, Delaglio F, Cornilescu G, Bax A (2009) TALOS + : a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts. J Biomol NMR 44(4):213–223

    Article  Google Scholar 

  54. Sudmeier JL, Bradshaw EM, Haddad KEC, Day RM, Thalhauser CJ, Bullock PA, Bachovchin WW (2003) Identification of histidine tautomers in proteins by 2D 1H/13C(delta2) one-bond correlated NMR. J Am Chem Soc 125(28):8430–8431

    Article  Google Scholar 

  55. Wishart DS, Case DA (2002) Use of chemical shifts in macromolecular structure determination. Methods Enzymol 338:3–34

    Article  Google Scholar 

  56. Wishart DS, Sykes BD (1994) The 13C chemical-shift index: a simple method for the identification of protein secondary structure using 13C chemical-shift data. J Biomol NMR 4(2):171–180

    Article  Google Scholar 

  57. Wishart DS, Bigam CG, Yao J, Abildgaard F, Dyson HJ, Oldfield E, Markley JL, Sykes BD (1995) 1H, 13C and 15 N chemical shift referencing in biomolecular NMR. J Biomol NMR 6(2):135–140

    Article  Google Scholar 

  58. Wishart DS, Arndt D, Berjanskii M, Tang P, Zhou J, Lin G (2008) CS23D: a web server for rapid protein structure generation using NMR chemical shifts and sequence data. Nucleic Acids Res 36(Web Server issue):W496–W502

    Google Scholar 

  59. Wuthrich K (1986) NMR of proteins and nucleic acids. Wiley, New York

    Google Scholar 

  60. Xia B, Cheng H, Skjeldal L, Coghlan VM, Vickery LE, Markley JL (1995) Multinuclear magnetic resonance and mutagenesis studies of the histidine residues of human mitochondrial ferredoxin. Biochemistry 34(1):180–187

    Article  Google Scholar 

  61. Zeng L, Yap KL, Ivanov AV, Wang X, Mujtaba S, Plotnikova O, Rauscher R, Frank J, Zhou M–M (2008) Structural insights into human KAP1 PHD finger-bromodomain and its role in gene silencing. Nat Struct Mol Biol 15(6):626–633

    Article  Google Scholar 

  62. Zhang H, Neal S, Wishart DS (2003) RefDB: a database of uniformly referenced protein chemical shifts. J Biomol NMR 25(3):173–195

    Article  Google Scholar 

Download references

Acknowledgments

We are grateful to Thomas Aeschbacher, Fionna Loughlin and Lawrence P. McIntosh for helpful discussions. Research in the Allain laboratory is supported by the Swiss National Science Foundation (Nr 31003E−131031) and the SNF-NCCR structural biology. P.B. was supported by the Postdoctoral ETH Fellowship Program. Author contributions: P.B. designed the project and analyzed the data; P.B., M.S. and F.H.-T.A. wrote the manuscript; all authors discussed the results and approved the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Pierre Barraud or Frédéric H.-T. Allain.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 135 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Barraud, P., Schubert, M. & Allain, F.HT. A strong 13C chemical shift signature provides the coordination mode of histidines in zinc-binding proteins. J Biomol NMR 53, 93–101 (2012). https://doi.org/10.1007/s10858-012-9625-6

Download citation

Keywords

  • NMR spectroscopy
  • 13C chemical shifts
  • Histidine
  • Zn-ligated histidine
  • Zinc-binding protein
  • Coordination mode of histidine
  • Histidine tautomers
  • Chemical shift analysis