A thermodynamic scale for leucine zipper stability and dimerization specificity: e and g interhelical interactions

EMBO J. 1994 Jun 15;13(12):2849-61.


The leucine zipper is a dimeric coiled-coil protein structure composed of two amphipathic alpha-helices with the hydrophobic surfaces interacting to create the dimer interface. This structure has been found to mediate the dimerization of two abundant classes of DNA binding proteins: the bZIP and bHLH-Zip proteins. Several workers have reported that amino acids in the e and g positions of the coiled coil can modulate dimerization stability and specificity. Using the bZIP protein VBP as a host molecule, we report a thermodynamic scale (delta delta G) for 27 interhelical interactions in 35 proteins between amino acids in the g and the following e positions (g<==>e') of a leucine zipper coiled coil. We have examined the four commonly occurring amino acids in the e and g positions of bZIP proteins, lysine (K), arginine (R), glutamine (Q), glutamic acid (E), as well as the only other remaining charged amino acid aspartic acid (D), and finally alanine (A) as a reference amino acid. These results indicate that E<==>R is the most stable interhelical pair, being 0.35 kcal/mol more stable than E<==>K. A thermodynamic cycle analysis shows that the E<==>R pair is 1.33 kcal/mol more stable than A<==>A with -1.14 kcal/mol of coupling energy (delta delta Gint) coming from the interaction of E with R. The E<==>K coupling energy is only -0.14 kcal/mol. E interacts with more specificity than Q. The R<==>R pair is less stable than the K<==>K by 0.24 kcal/mol. R interacts with more specificity than K. Q forms more stable pairs with the basic amino acids K and R rather than with E. Changing amino acids in the e position to A creates bZIP proteins that form tetramers.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Avian Proteins*
  • Basic-Leucine Zipper Transcription Factors
  • Carrier Proteins / chemistry
  • Centrifugation, Isopycnic
  • Circular Dichroism
  • DNA-Binding Proteins / chemistry*
  • G-Box Binding Factors
  • Helix-Loop-Helix Motifs
  • Leucine Zippers*
  • Models, Chemical
  • Molecular Sequence Data
  • Protein Denaturation
  • Protein Structure, Tertiary*
  • Recombinant Proteins / chemistry
  • Thermodynamics
  • Transcription Factors / chemistry


  • Avian Proteins
  • Basic-Leucine Zipper Transcription Factors
  • Carrier Proteins
  • DNA-Binding Proteins
  • G-Box Binding Factors
  • Recombinant Proteins
  • Transcription Factors