Molecular basis of coiled-coil formation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-04, Vol.104 (17), p.7062-7067
• Main Authors: Steinmetz, Michel O, Jelesarov, Ilian, Matousek, William M, Honnappa, Srinivas, Jahnke, Wolfgang, Missimer, John H, Frank, Sabine, Alexandrescu, Andrei T, Kammerer, Richard A
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution; Arginine; Basic-Leucine Zipper Transcription Factors; Biochemistry; Biological Sciences; Biophysics; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - metabolism; Hydrogen-Ion Concentration; Kinetics; Leucine Zippers; Magnetic Resonance Spectroscopy; Molecules; Mutant Proteins - chemistry; Peptides - chemistry; Protein Folding; Proteins; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - metabolism; Solutions; Thermodynamics; Transcription Factors - chemistry; Transcription Factors - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0700321104

Coiled coils have attracted considerable interest as design templates in a wide range of applications. Successful coiled-coil design strategies therefore require a detailed understanding of coiled-coil folding. One common feature shared by coiled coils is the presence of a short autonomous helical folding unit, termed "trigger sequence," that is indispensable for folding. Detailed knowledge of trigger sequences at the molecular level is thus key to a general understanding of coiled-coil formation. Using a multidisciplinary approach, we identify and characterize here the molecular determinants that specify the helical conformation of the monomeric early folding intermediate of the GCN4 coiled coil. We demonstrate that a network of hydrogen-bonding and electrostatic interactions stabilize the trigger-sequence helix. This network is rearranged in the final dimeric coiled-coil structure, and its destabilization significantly slows down GCN4 leucine zipper folding. Our findings provide a general explanation for the molecular mechanism of coiled-coil formation.