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Switching from the unfolded to the folded state of the helix‐loop‐helix domain of the Id proteins based on the O ‐acyl isopeptide method
Author(s) -
Kiewitz Sebastian D.,
Kakizawa Taeko,
Kiso Yoshiaki,
Cabrele Chiara
Publication year - 2008
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.1059
Subject(s) - basic helix loop helix , helix (gastropod) , chemistry , serine , peptide , transcription factor , random coil , coiled coil , residue (chemistry) , helix turn helix , biophysics , stereochemistry , microbiology and biotechnology , biochemistry , protein secondary structure , dna binding protein , biology , gene , phosphorylation , ecology , snail
The inhibitors of DNA binding and cell differentiation Id1–4 are helix‐loop‐helix (HLH) proteins that negatively regulate DNA transcription by forming inactive dimers with ubiquitous and tissue‐specific bHLH proteins, including E47 and MyoD, respectively. Their highly conserved HLH domains are essential for heterodimerization, but can also self‐associate to highly stable, α‐helix‐rich structures at low micromolar peptide concentrations. Here, we show that the introduction of an O ‐acyl isodipeptide unit involving the putative N ‐cap serine residue of the C ‐terminal helix completely abrogates the propensity of the Id HLH analogue for any secondary and tertiary structure, resulting in a random coil, as shown by CD measurements in nonbuffered aqueous solutions. However, the HLH fold reappears as soon as an O → N intramolecular acyl migration, which occurs spontaneously under physiological conditions, restores the native N ‐cap serine residue. These results show that changes addressing the N ‐terminus of the C ‐terminal helix can dramatically influence the HLH structure, and suggest that local interactions at the junction between the loop and the C ‐terminal helix might be crucial during the HLH folding process. Furthermore, the present study contributes to the evaluation of the O ‐acyl isodipeptide unit as a powerful tool to introduce a conformational switch into peptides. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd.