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The hidden thermodynamics of a zinc finger.

Lachenmann MJ, Ladbury JE, Phillips NB, Narayana N, Qian X, Weiss MA
J Mol Biol 316 969-89 (2002)
Cited: 22 times
EuropePMC logo PMID: 11884136

Abstract

The Zn finger provides a model for studies of protein structure and stability. Its core contains a conserved phenylalanine residue adjoining three architectural elements: a beta-hairpin, an alpha-helix and a tetrahedral Zn(2+)-binding site. Here, we demonstrate that the consensus Phe is not required for high-affinity Zn(2+) binding but contributes to the specification of a precise DNA-binding surface. Substitution of Phe by leucine in a ZFY peptide permits Zn(2+)-dependent folding. Although a native-like structure is retained, structural fluctuations lead to attenuation of selected nuclear Overhauser enhancements and accelerated amide proton exchange. Surprisingly, wild-type Zn affinity is maintained by entropy-enthalpy compensation (EEC): a hidden entropy penalty (TDeltaDeltaS 7kcal/mol) is balanced by enhanced enthalpy of association (DeltaDeltaH -7kcal/mol) at 25 degrees C. Because the variant is less well ordered than the Phe-anchored domain, the net change in entropy is opposite to the apparent change in configurational entropy. By analogy to the thermodynamics of organometallic complexation, we propose that EEC arises from differences in solvent reorganization. Exclusion of Leu among biological sequences suggests an evolutionary constraint on the dynamics of a Zn finger.

Reviews citing this publication (2)

  1. Relationship between the architecture of zinc coordination and zinc binding affinity in proteins--insights into zinc regulation. Kochańczyk T, Drozd A, Krężel A. Metallomics 7 244-257 (2015)
  2. A survey of the year 2002 literature on applications of isothermal titration calorimetry. Cliff MJ, Ladbury JE. J Mol Recognit 16 383-391 (2003)

Articles citing this publication (20)

  1. How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor. Huang K, Xu B, Hu SQ, Chu YC, Hua QX, Qu Y, Li B, Wang S, Wang RY, Nakagawa SH, Theede AM, Whittaker J, De Meyts P, Katsoyannis PG, Weiss MA. J Mol Biol 341 529-550 (2004)
  2. Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation. Cordier F, Vinolo E, Véron M, Delepierre M, Agou F. J Mol Biol 377 1419-1432 (2008)
  3. Solution structure of a Zap1 zinc-responsive domain provides insights into metalloregulatory transcriptional repression in Saccharomyces cerevisiae. Wang Z, Feng LS, Matskevich V, Venkataraman K, Parasuram P, Laity JH. J Mol Biol 357 1167-1183 (2006)
  4. Thermodynamic consequences of disrupting a water-mediated hydrogen bond network in a protein:pheromone complex. Sharrow SD, Edmonds KA, Goodman MA, Novotny MV, Stone MJ. Protein Sci 14 249-256 (2005)
  5. Specific DNA recognition by a synthetic, monomeric Cys2His2 zinc-finger peptide conjugated to a minor-groove binder. Vázquez O, Vázquez ME, Blanco JB, Castedo L, Mascareñas JL. Angew Chem Int Ed Engl 46 6886-6890 (2007)
  6. Electrostatics dominate quadruplex stability. Smirnov IV, Shafer RH. Biopolymers 85 91-101 (2007)
  7. A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide- and tumor necrosis factor-mediated NF-kappa B activation. Vinolo E, Sebban H, Chaffotte A, Israël A, Courtois G, Véron M, Agou F. J Biol Chem 281 6334-6348 (2006)
  8. Induced fit and the entropy of structural adaptation in the complexation of CAP and lambda-repressor with cognate DNA sequences. Dixit SB, Andrews DQ, Beveridge DL. Biophys J 88 3147-3157 (2005)
  9. Metal binding properties of the zinc finger metallome--insights into variations in stability. Miłoch A, Krężel A. Metallomics 6 2015-2024 (2014)
  10. Cysteine and histidine shuffling: mixing and matching cysteine and histidine residues in zinc finger proteins to afford different folds and function. Michalek JL, Besold AN, Michel SL. Dalton Trans 40 12619-12632 (2011)
  11. Identification and characterization of a consensus DNA binding element for the zinc finger transcription factor TIEG/EGRalpha. Chrisman HR, Tindall DJ. DNA Cell Biol 22 187-199 (2003)
  12. Regulation of sexual dimorphism: mutational and chemogenetic analysis of the doublesex DM domain. Zhang W, Li B, Singh R, Narendra U, Zhu L, Weiss MA. Mol Cell Biol 26 535-547 (2006)
  13. Characterization of the Zn(II) binding properties of the human Wilms' tumor suppressor protein C-terminal zinc finger peptide. Chan KL, Bakman I, Marts AR, Batir Y, Dowd TL, Tierney DL, Gibney BR. Inorg Chem 53 6309-6320 (2014)
  14. On the design of zinc-finger models with cyclic peptides bearing a linear tail. Jacques A, Mettra B, Lebrun V, Latour JM, Sénèque O. Chemistry 19 3921-3931 (2013)
  15. Solvation and the hidden thermodynamics of a zinc finger probed by nonstandard repair of a protein crevice. Lachenmann MJ, Ladbury JE, Qian X, Huang K, Singh R, Weiss MA. Protein Sci 13 3115-3126 (2004)
  16. Non-Conserved Amino Acid Residues Modulate the Thermodynamics of Zn(II) Binding to Classical ββα Zinc Finger Domains. Kluska K, Chorążewska A, Peris-Díaz MD, Adamczyk J, Krężel A. Int J Mol Sci 23 14602 (2022)
  17. Separating the role of protein restraints and local metal-site interaction chemistry in the thermodynamics of a zinc finger protein. Dixit PD, Asthagiri D. Biophys J 101 1459-1466 (2011)
  18. Proteomimetic Zinc Finger Domains with Modified Metal-binding β-Turns. Rao SR, Horne WS. Pept Sci (Hoboken) 112 (2020)
  19. High five! Methyl probes at five ring positions of phenylalanine explore the hydrophobic core dynamics of zinc finger miniproteins. Horx P, Geyer A. Chem Sci 12 11455-11463 (2021)
  20. Tenuous transcriptional threshold of human sex determination. II. SRY exploits water-mediated clamp at the edge of ambiguity. Racca JD, Chatterjee D, Chen YS, Rai RK, Yang Y, Georgiadis MM, Haas E, Weiss MA. Front Endocrinol (Lausanne) 13 1029177 (2022)


Related citations provided by authors (1)

  1. Two-dimensional NMR studies of the zinc finger motif: solution structures and dynamics of mutant ZFY domains containing aromatic substitutions in the hydrophobic core. Qian X, Weiss MA Biochemistry 31 7463-7476 (1992)

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