TAILIEUCHUNG - Báo cáo khoa học: Electrostatic contacts in the activator protein-1 coiled coil enhance stability predominantly by decreasing the unfolding rate

The hypothesis is tested that Jun–Fos activator protein-1 coiled coil inter-actions are dominated during late folding events by the formation of intri-cate 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. | ỊFEBS Journal Electrostatic contacts in the activator protein-1 coiled coil enhance stability predominantly by decreasing the unfolding rate Jody M. Mason Department of BiologicalSciences University of Essex Colchester UK Keywords activator protein-1 coiled coils electrostatic interactions protein design protein folding Correspondence J. M. Mason Department of Biological Sciences University of Essex Wivenhoe Park Colchester Essex CO4 3SQ UK Fax 44 1206 872 592 Tel 44 1206 873 010 E-mail jmason@ Received 2 September 2009 revised 9 October 2009 accepted 15 October 2009 doi 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. Introduction The primary factors governing protein-protein interaction stability have yet to be fully elucidated. To this end our focus continues on the coiled coil region of the activator protein-1 AP-1 transcription factor. Coiled coils are one of the more tractable examples of quaternary .

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