Metal binding mediated conformational change of XPA protein:a potential cytotoxic mechanism of nickel in the nucleotide excision repair

Original Paper

Abstract

Nucleotide excision repair (NER) is a pivotal life process for repairing DNA nucleotide mismatch caused by chemicals, metal ions, radiation, and other factors. As the initiation step of NER, the xeroderma pigmentosum complementation group A protein (XPA) recognizes damaged DNA molecules, and recruits the replication protein A (RPA), another important player in the NER process. The stability of the Zn2+-chelated Zn-finger domain of XPA center core portion (i.e., XPA98-210) is the foundation of its biological functionality, while the displacement of the Zn2+ by toxic metal ions (such as Ni2+, a known human carcinogen and allergen) may impair the effectiveness of NER and hence elevate the chance of carcinogenesis. In this study, we first calculated the force field parameters for the bonded model in the metal center of the XPA98-210 system, showing that the calculated results, including charges, bonds, angles etc., are congruent with previously reported results measured by spectrometry experiments and quantum chemistry computation. Then, comparative molecular dynamics simulations using these parameters revealed the changes in the conformation and motion mode of XPA98-210 Zn-finger after the substitution of Zn2+ by Ni2+. The results showed that Ni2+ dramatically disrupted the relative positions of the four Cys residues in the Zn-finger structure, forcing them to collapse from a tetrahedron into an almost planar structure. Finally, we acquired the binding mode of XPA98-210 with its ligands RPA70N and DNA based on molecular docking and structural alignment. We found that XPA98-210’s Zn-finger domain primarily binds to a V-shaped cleft in RPA70N, while the cationic band in its C-terminal subdomain participates in the recognition of damaged DNA. In addition, this article sheds light on the multi-component interaction pattern among XPA, DNA, and other NER-related proteins (i.e., RPA70N, RPA70A, RPA70B, RPA70C, RPA32, and RPA14) based on previously reported structural biology information. Thus, we derived a putative cytotoxic mechanism associated with the nickel ion, where the Ni2+ disrupts the conformation of the XPA Zn-finger, directly weakening its interaction with RPA70N, and thus lowering the effectiveness of the NER process. In sum, this work not only provides a theoretical insight into the multi-protein interactions involved in the NER process and potential cytotoxic mechanism associated with Ni2+ binding in XPA, but may also facilitate rational anti-cancer drug design based on the NER mechanism.

Keywords

Cytotoxic mechanism Nickel ion Nucleotide excision repair XPA Zn-finger 

Supplementary material

894_2016_3017_MOESM1_ESM.docx (4.2 mb)
ESM 1(DOCX 4.22 mb)

References

  1. 1.
    Sanear A (1994) Mechanisms of DNA excision repair. Science 266:1954–1956CrossRefGoogle Scholar
  2. 2.
    Gillet LC, Schärer OD (2006) Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem Rev 106:253–276CrossRefGoogle Scholar
  3. 3.
    Li L, Lu X, Peterson CA, Legerski RJ (1995) An interaction between the DNA repair factor XPA and replication protein A appears essential for nucleotide excision repair. Mol Cell Biol 15:5396–5402CrossRefGoogle Scholar
  4. 4.
    Feltes BC, Bonatto D (2015) Overview of xeroderma pigmentosum proteins architecture, mutations and post-translational modifications. Mutat Res Rev Mut Res 763:306–320CrossRefGoogle Scholar
  5. 5.
    Geacintov NE, Broyde S, Buterin T, Naegeli H, Wu M, Yan S, Patel DJ (2002) Thermodynamic and structural factors in the removal of bulky DNA adducts by the nucleotide excision repair machinery. Biopolymers 65:202–210CrossRefGoogle Scholar
  6. 6.
    Koch SC, Kuper J, Gasteiger KL, Simon N, Strasser R, Eisen D, Geiger S, Schneider S, Kisker C, Carell T (2015) Structural insights into the recognition of cisplatin and AAF-dG lesion by Rad14 (XPA). Proc Natl Acad Sci U S A 112:8272–8277CrossRefGoogle Scholar
  7. 7.
    Oei AL, Vriend LE, Crezee J, Franken NA, Krawczyk PM (2015) Effects of hyperthermia on DNA repair pathways: one treatment to inhibit them all. Radiat Oncol 10:165–179CrossRefGoogle Scholar
  8. 8.
    Sugitani N, Chazin WJ (2015) Characteristics and concepts of dynamic hub proteins in DNA processing machinery from studies of RPA. Prog Biophys Mol Biol 117:206–211CrossRefGoogle Scholar
  9. 9.
    Li CL, Golebiowski FM, Onishi Y, Samara NL, Sugasawa K, Yang W (2015) Tripartite DNA lesion recognition and verification by XPC, TFIIH, and XPA in nucleotide excision repair. Mol Cell 59:1025–1034CrossRefGoogle Scholar
  10. 10.
    Hilton B, Shkriabai N, Musich PR, Kvaratskhelia M, Shell S, Zou Y (2014) A new structural insight into XPA-DNA interactions. Biosci Rep 34:831–840CrossRefGoogle Scholar
  11. 11.
    Jones CJ, Wood RD (1993) Preferential binding of the xeroderma pigmentosum group A complementing protein to damaged DNA. Biochemistry 32:12096–12104CrossRefGoogle Scholar
  12. 12.
    Ikegami T, Kuraoka I, Saijo M, Kodo N, Kyogoku Y, Morikawa K, Tanaka K, Shirakawa M (1998) Solution structure of the DNA-and RPA-binding domain of the human repair factor XPA. Nat Struct Mol Biol 5:701–706CrossRefGoogle Scholar
  13. 13.
    Buchko GW, Daughdrill GW, De Lorimier R, Sudha Rao B, Isern NG, Lingbeck JM, Taylor JS, Wold MS, Gochin M, Spicer LD (1999) Interactions of human nucleotide excision repair protein XPA with DNA and RPA70ΔC327: Chemical shift mapping and 15N NMR relaxation studies. Biochemistry 38:15116–15128CrossRefGoogle Scholar
  14. 14.
    Bochkareva E, Korolev S, Lees-Miller SP, Bochkarev A (2002) Structure of the RPA trimerization core and its role in the multistep DNA‐binding mechanism of RPA. EMBO J 21:1855–1863CrossRefGoogle Scholar
  15. 15.
    He Z, Henricksen LA, Wold MS, Ingles CJ (1995) RPA involvement in the damage-recognition and incision steps of nucleotide excision repair. Nature 374:566–569CrossRefGoogle Scholar
  16. 16.
    Aboussekhra A, Biggerstaff M, Shivji MK, Vilpo JA, Moncollin V, Podust VN, Protić M, Hübscher U, Egly JM, Wood RD (1995) Mammalian DNA nucleotide excision repair reconstituted with purified protein components. Cell 80:859–868CrossRefGoogle Scholar
  17. 17.
    Hey T, Lipps G, Krauss G (2001) Binding of XPA and RPA to damaged DNA investigated by fluorescence anisotropy. Biochemistry 40:2901–2910CrossRefGoogle Scholar
  18. 18.
    Wang M, Mahrenholz A, Lee SH (2000) RPA stabilizes the XPA-damaged DNA complex through protein-protein interaction. Biochemistry 39:6433–6439CrossRefGoogle Scholar
  19. 19.
    Sakharov DV, Lim C (2005) Zn protein simulations including charge transfer and local polarization effects. J Am Chem Soc 127:4921–4929CrossRefGoogle Scholar
  20. 20.
    Michalek JL, Besold AN, Michel SL (2011) Cysteine and histidine shuffling: mixing and matching cysteine and histidine residues in zinc finger proteins to afford different folds and function. Dalton Trans 40:12619–12632CrossRefGoogle Scholar
  21. 21.
    Besold AN, Lee SJ, Michel SL, Sue NL, Cymet HJ (2010) Functional characterization of iron-substituted neural zinc finger factor 1: metal and DNA binding. J Biol Inorg Chem 15:583–590CrossRefGoogle Scholar
  22. 22.
    Witkiewicz-Kucharczyk A, Bal W (2006) Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis. Toxicol Lett 162:29–42CrossRefGoogle Scholar
  23. 23.
    Asmuss M, Mullenders LH, Eker A, Hartwig A (2000) Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair. Carcinogenesis 21:2097–2104CrossRefGoogle Scholar
  24. 24.
    Hartwig A, Asmuss M, Ehleben I, Herzer U, Kostelac D, Pelzer A, Schwerdtle T, Bürkle A (2002) Interference by toxic metal ions with DNA repair processes and cell cycle control: molecular mechanisms. Environ Health Perspect 110:797–799CrossRefGoogle Scholar
  25. 25.
    Cleaver J (1997) The DNA damage-recognition problem in human and other eukaryotic cells: the XPA damage binding protein. Biochem J 328:1–12CrossRefGoogle Scholar
  26. 26.
    Asahina H, Kuraoka I, Shirakawa M, Morita EH, Miura N, Miyamoto I, Ohtsuka E, Okada Y, Tanaka K (1994) The XPA protein is a zinc metalloprotein with an ability to recognize various kinds of DNA damage. Mutat Res/DNA Repair 315:229–237CrossRefGoogle Scholar
  27. 27.
    Hartwig A (1998) Carcinogenicity of metal compounds: possible role of DNA repair inhibition. Toxicol Lett 102:235–239CrossRefGoogle Scholar
  28. 28.
    Hartwig A (2001) Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid Redox Signal 3:625–634CrossRefGoogle Scholar
  29. 29.
    Li P, Roberts BP, Chakravorty DK, Merz KM Jr (2013) Rational design of particle mesh Ewald compatible Lennard-Jones parameters for + 2 metal cations in explicit solvent. J Chem Theory Comput 9:2733–2748CrossRefGoogle Scholar
  30. 30.
    Pang YP (2001) Successful molecular dynamics simulation of two zinc complexes bridged by a hydroxide in phosphotriesterase using the cationic dummy atom method. Proteins: Struct Funct Bioinform 45:183–189CrossRefGoogle Scholar
  31. 31.
    Peters MB, Yang Y, Wang B, Füsti-Molnár L, Weaver MN, Merz KM Jr (2010) Structural survey of zinc-containing proteins and development of the zinc AMBER force field (ZAFF). J Chem Theory Comput 6:2935–2947CrossRefGoogle Scholar
  32. 32.
    Hou TJ, Zhang W, Xu XJ (2001) Binding affinities for a series of selective inhibitors of gelatinase-A using molecular dynamics with a linear interaction energy approach. J Phys Chem B 105:5304–5315CrossRefGoogle Scholar
  33. 33.
    Tounge BA, Reynolds CH (2003) Calculation of the binding affinity of β-secretase inhibitors using the linear interaction energy method. J Med Chem 46:2074–2082CrossRefGoogle Scholar
  34. 34.
    Zhou M, Du K, Ji P, Feng W (2012) Molecular mechanism of the interactions between inhibitory tripeptides and angiotensin-converting enzyme. Biophys Chem 168:60–66CrossRefGoogle Scholar
  35. 35.
    Case DA, Darden TA, Cheatham TE III, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Götz AW, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh MJ, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Pa K (2012) AMBER 12. University of California, San FranciscoGoogle Scholar
  36. 36.
    Becke AD (1993) Density-functional thermochemistry. III. the role of exact exchange. J Chem Phys 98:5648–5652CrossRefGoogle Scholar
  37. 37.
    Dill JD, Pople JA (1975) Self‐consistent molecular orbital methods. XV. extended Gaussian-type basis sets for lithium, beryllium, and boron. J Chem Phys 62:2921–2923CrossRefGoogle Scholar
  38. 38.
    Frisch M, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J, Montgomery J Jr, Vreven T, Kudin K, Burant J et al. (2004) Gaussian 03. Gaussian Inc., WallingfordGoogle Scholar
  39. 39.
    Feng Z, Kochanek S, Close D, Wang L, Srinivasan A, Almehizia AA, Iyer P, Xie X-Q, Johnston PA, Gold B (2015) Design and activity of AP endonuclease-1 inhibitors. J Chem Biol: 1–15Google Scholar
  40. 40.
    Feng Z, Pearce LV, Xu X, Yang X, Yang P, Blumberg PM, Xie X-Q (2015) Structural insight into tetrameric hTRPV1 from homology modeling, molecular docking, molecular dynamics simulation, virtual screening, and bioassay validations. J Chem Inf Model 55:572–588CrossRefGoogle Scholar
  41. 41.
    Feng Z, Alqarni MH, Yang P, Tong Q, Chowdhury A, Wang L, Xie X-Q (2014) Modeling, molecular dynamics simulation, and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs. J Chem Inf Model 54:2483–2499CrossRefGoogle Scholar
  42. 42.
    Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688CrossRefGoogle Scholar
  43. 43.
    Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the Amber ff99SB protein force field. Proteins: Struct Funct Bioinform 78:1950–1958Google Scholar
  44. 44.
    Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935CrossRefGoogle Scholar
  45. 45.
    Shen R, Han W, Fiorin G, Islam SM, Schulten K, Roux B (2015) Structural refinement of proteins by restrained molecular dynamics simulations with non-interacting molecular fragments. PLoS Comput Biol 11:e1004368CrossRefGoogle Scholar
  46. 46.
    Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341CrossRefGoogle Scholar
  47. 47.
    Amadei A, Linssen A, De Groot B, Van Aalten D, Berendsen H (1996) An efficient method for sampling the essential subspace of proteins. J Biomol Struct Dyn 13:615–625CrossRefGoogle Scholar
  48. 48.
    Hu JP, Wang CX (2010) Molecular dynamics simulation of HIV-1 integrase dimer complexed with viral DNA. Chin J Chem 28:33–40CrossRefGoogle Scholar
  49. 49.
    Wan H, Chang S, Hu JP, Tian YX, Tian XH (2015) Molecular dynamics simulations of ternary complexes: comparisons of LEAFY protein binding to different DNA motifs. J Chem Inf Model 55:784–794CrossRefGoogle Scholar
  50. 50.
    Srikumar P, Rohini K, Rajesh PK (2014) Molecular dynamics simulations and principal component analysis on human laforin mutation W32G and W32G/K87A. Protein J 33:289–295CrossRefGoogle Scholar
  51. 51.
    Nagai T, Mitsutake A, Takano H (2013) Principal component relaxation mode analysis of an all-atom molecular dynamics simulation of human lysozyme. J Phys Soc Jpn 82:023803CrossRefGoogle Scholar
  52. 52.
    Ivanov PM (2010) Conformations of some large-ring cyclodextrins derived from conformational search with molecular dynamics simulations and principal component analysis. J Phys Chem B 114:2650–2659CrossRefGoogle Scholar
  53. 53.
    Maisuradze GG, Liwo A, Scheraga HA (2010) Relation between free energy landscapes of proteins and dynamics. J Chem Theory Comput 6:583–595CrossRefGoogle Scholar
  54. 54.
    Wan H, Hu JP, Li KS, Tian XH, Chang S (2013) Molecular dynamics simulations of DNA-free and DNA-bound TAL effectors. PLoS One 8:e76045CrossRefGoogle Scholar
  55. 55.
    Wan H, Hu JP, Tian XH, Chang S (2013) Molecular dynamics simulations of wild type and mutants of human complement receptor 2 complexed with C3d. Phys Chem Chem Phys 15:1241–1251CrossRefGoogle Scholar
  56. 56.
    Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ (2005) GROMACS: fast, flexible, and free. J Comput Chem 26:1701–1718CrossRefGoogle Scholar
  57. 57.
    Bayly CI, Cieplak P, Cornell W, Kollman PA (1993) A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J Phys Chem 97:10269–10280CrossRefGoogle Scholar
  58. 58.
    Woods RJ, Khalil M, Pell W, Moffat SH, Smith VH (1990) Derivation of net atomic charges from molecular electrostatic potentials. J Comput Chem 11:297–310CrossRefGoogle Scholar
  59. 59.
    Sindhikara DJ, Roitberg AE, Merz KM Jr (2009) Apo and nickel-bound forms of the Pyrococcus horikoshii species of the metalloregulatory protein: NikR characterized by molecular dynamics simulations. Biochemistry 48:12024–12033CrossRefGoogle Scholar
  60. 60.
    Ni C, Dang D, Song Y, Gao S, Li Y, Ni Z, Tian Z, Wen L, Meng Q (2004) An interesting magnetic behavior in molecular solid containing one-dimensional Ni (III) chain. Chem Phys Lett 396:353–358CrossRefGoogle Scholar
  61. 61.
    Liu S, Han YF, Jin GX (2007) Formation of direct metal–metal bonds from 16-electron “pseudo-aromatic” half-sandwich complexes Cp ″M [E 2 C 2 (B 10 H 10)]. Chem Soc Rev 36:1543–1560CrossRefGoogle Scholar
  62. 62.
    Feig M, Karanicolas J, Brooks CL (2004) MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology. J Mol Graphics Modell 22:377–395CrossRefGoogle Scholar
  63. 63.
    Kabsch W, Sander C (1983) Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22:2577–2637CrossRefGoogle Scholar
  64. 64.
    Andersen CA, Palmer AG, Brunak S, Rost B (2002) Continuum secondary structure captures protein flexibility. Structure 10:175–184CrossRefGoogle Scholar
  65. 65.
    Tripsianes K, Folkers GE, Zheng C, Das D, Grinstead JS, Kaptein R, Boelens R (2007) Analysis of the XPA and ssDNA-binding surfaces on the central domain of human ERCC1 reveals evidence for subfunctionalization. Nucleic Acids Res 35:5789–5798CrossRefGoogle Scholar
  66. 66.
    Naegeli H, Sugasawa K (2011) The xeroderma pigmentosum pathway: decision tree analysis of DNA quality. DNA Repair 10:673–683CrossRefGoogle Scholar
  67. 67.
    Buchko GW, Isern NG, Spicer LD, Kennedy MA (2001) Human nucleotide excision repair protein XPA: NMR spectroscopic studies of an XPA fragment containing the ERCC1-binding region and the minimal DNA-binding domain (M59-F219). Mutat Res/DNA Repair 486:1–10CrossRefGoogle Scholar
  68. 68.
    Maltseva E, Krasikova Y, Naegeli H, Lavrik O, Rechkunova N (2014) Effect of point substitutions within the minimal DNA-binding domain of xeroderma pigmentosum group a protein on interaction with DNA intermediates of nucleotide excision repair. Biochem Mosc 79:545–554CrossRefGoogle Scholar
  69. 69.
    Sugitani N, Shell SM, Soss SE, Chazin WJ (2014) Redefining the DNA-binding domain of human XPA. J Am Chem Soc 136:10830–10833CrossRefGoogle Scholar
  70. 70.
    Bochkareva E, Belegu V, Korolev S, Bochkarev A (2001) Structure of the major single‐stranded DNA‐binding domain of replication protein A suggests a dynamic mechanism for DNA binding. EMBO J 20:612–618CrossRefGoogle Scholar
  71. 71.
    Bochkarev A, Pfuetzner RA, Edwards AM, Frappier L (1997) Structure of the single-stranded-DNA-binding domain of replication protein A bound to DNA. Nature 385:176–181CrossRefGoogle Scholar
  72. 72.
    Frank AO, Vangamudi B, Feldkamp MD, Souza-Fagundes EM, Luzwick JW, Cortez D, Olejniczak ET, Waterson AG, Rossanese OW, Chazin WJ (2014) Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A. J Med Chem 57:2455–2461CrossRefGoogle Scholar
  73. 73.
    Bochkareva E, Kaustov L, Ayed A, Yi GS, Lu Y, Pineda-Lucena A, Liao JC, Okorokov AL, Milner J, Arrowsmith CH (2005) Single-stranded DNA mimicry in the p53 transactivation domain interaction with replication protein A. Proc Natl Acad Sci U S A 102:15412–15417CrossRefGoogle Scholar
  74. 74.
    Pierce BG, Wiehe K, Hwang H, Kim BH, Vreven T, Weng Z (2014) ZDOCK server: interactive docking prediction of protein–protein complexes and symmetric multimers. Bioinformatics 30:1771–1773CrossRefGoogle Scholar
  75. 75.
    Pierce BG, Hourai Y, Weng Z (2011) Accelerating protein docking in ZDOCK using an advanced 3D convolution library. PLoS One 6:e24657CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.College of ChemistryLeshan Normal UniversityLeshanChina
  2. 2.Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy; NIH National Center of Excellence for Computational Drug Abuse Research; Drug Discovery Institute; Department of Computational Biology and Structural Biology, School of MedicineUniversity of PittsburghPittsburghUSA
  3. 3.School of Pharmacy and Bioengineering; Key Laboratory of Medicinal and Edible Plants Resources Development, School of BioengineeringChengdu UniversityChengduChina
  4. 4.Division of Biology, Chemistry, and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological HealthU.S. Food and Drug AdministrationSilver SpringUSA
  5. 5.School of PharmacyUniversity of PittsburghPittsburghUSA

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