Conformational energy analysis of the leucine repeat regions of C/EBP, GCN4, and the proteins of the myc, jun, and fos oncogenes.
It has been recently proposed that certain DNA binding proteins (including C/EBP, GCN4 and the myc, jun, and fos oncogene proteins) share a common structural motif based on helix-promoting regions containing heptad repeat sequences of leucines. It has been suggested that this structure is critical to the biological activity of these proteins, since it facilitates the formation of functional dimers held together by interdigitating leucine side-chains along the hydrophobic interfaces between long alpha-helical regions of the polypeptide chains in a configuration termed the "leucine zipper." In this paper, conformational energy analysis is used to deterrmine the preferred three-dimensional structures of the leucine repeat regions of these proteins. The results indicate that, in all cases, the global minimum energy conformation for these regions is an amphipathic alpha-helix with the leucine side-chains arrayed on one side in such a way to favor "leucine zipper" dimerization. Furthermore, amino acid substitutions in these regions (such as Pro for Leu), that are known to inhibit dimer formation and prevent DNA binding, are found to produce significant conformational changes that disrupt the amphipathic helical structure. Thus, these results provide support for the proposed "leucine zipper" configuration as a critical structural feature of this class of DNA binding proteins.
Brandt-Rauf
P W
PW
Division of Environmental Sciences, Columbia-Presbyterian Medical Center, New York, New York 10032.
Pincus
M R
MR
Chen
J M
JM
Lee
G
G
D000595:Amino Acid Sequence; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D007930:Leucine; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D016274:Oncogene Protein p55(v-myc); D016759:Oncogene Protein p65(gag-jun); D015513:Oncogene Proteins; D016761:Oncogene Proteins v-fos; D009856:Oncogene Proteins, Viral; D011487:Protein Conformation; D011494:Protein Kinases; D015682:Retroviridae Proteins, Oncogenic; D029701:Saccharomyces cerevisiae Proteins; D013816:Thermodynamics; D014157:Transcription Factors
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D009687:Nuclear Proteins; D016274:Oncogene Protein p55(v-myc); D016759:Oncogene Protein p65(gag-jun); D015513:Oncogene Proteins; D016761:Oncogene Proteins v-fos; D009856:Oncogene Proteins, Viral; D015682:Retroviridae Proteins, Oncogenic; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011494:Protein Kinases; D007930:Leucine