Premium
Electrostatic contacts in the activator protein‐1 coiled coil enhance stability predominantly by decreasing the unfolding rate
Author(s) -
Mason Jody M.
Publication year - 2009
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2009.07440.x
Subject(s) - coiled coil , activator (genetics) , electrostatics , chemistry , crystallography , protein folding , kinetic energy , thermal stability , dissociation (chemistry) , biophysics , folding (dsp implementation) , electromagnetic coil , chemical physics , receptor , physics , biology , biochemistry , quantum mechanics , electrical engineering , organic chemistry , engineering
The hypothesis is tested that Jun–Fos activator protein‐1 coiled coil interactions are dominated during late folding events by the formation of intricate intermolecular electrostatic contacts. A previously derived cJun–FosW was used as a template as it is a highly stable relative of the wild‐type cJun–cFos coiled coil protein (thermal melting temperature = 63 °C versus 16 °C), allowing kinetic folding data to be readily extracted. An electrostatic mutant, cJun(R)–FosW(E), was created to generate six Arg‐Glu interactions at e–g ′+1 positions between cJun(R) and FosW(E), and investigations into how their contribution to stability is manifested in the folding pathway were undertaken. The evidence now strongly indicates that the formation of interhelical electrostatic contacts exert their effect predominantly on the coiled coil unfolding/dissociation rate. This has major implications for future antagonist design whereby kinetic rules could be applied to increase the residency time of the antagonist–peptide complex, and therefore significantly increase the efficacy of the antagonist.