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The effect of electrostatics on the marginal cooperativity of an ultrafast folding protein

AuthorsDesai, Tanay M.; Cerminara, Michele; Sadqi, Mourad; Muñoz, Víctor
Protein conformation
Protein folding
Protein stability
Downhill folding
Electrostatic screening
Ultrafast kinetics
Issue Date5-Nov-2010
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationThe Journal of Biological Chemistry 285 (45) 34549–34556 (2010)
AbstractProteins fold up by coordinating the different segments of their polypeptide chain through a network of weak cooperative interactions. Such cooperativity results in unfolding curves that are typically sigmoidal. However, we still do not know what factors modulate folding cooperativity or the minimal amount that ensures folding into specific three-dimensional structures. Here, we address these issues on BBL, a small helical protein that folds in microseconds via a marginally cooperative downhill process (Li, P., Oliva, F. Y., Naganathan, A. N., and Muñoz, V. (2009) Proc. Natl. Acad. Sci. USA. 106, 103-108). Particularly, we explore the effects of salt-induced screening of the electrostatic interactions in BBL at neutral pH and in acid-denatured BBL. Our results show that electrostatic screening stabilizes the native state of the neutral and protonated forms, inducing complete refolding of acid-denatured BBL. Furthermore, without net electrostatic interactions, the unfolding process becomes much less cooperative, as judged by the broadness of the equilibrium unfolding curve and the relaxation rate. Our experiments show that the marginally cooperative unfolding of BBL can still be made twice as broad while the protein retains its ability to fold into the native three-dimensional structure in microseconds. This result demonstrates experimentally that efficient folding does not require cooperativity, confirming predictions from theory and computer simulations and challenging the conventional biochemical paradigm. Furthermore, we conclude that electrostatic interactions are an important factor in determining folding cooperativity. Thus, electrostatic modulation by pH-salt and/or mutagenesis of charged residues emerges as an attractive tool for tuning folding cooperativity.
Description13 p.-5 fig.-1 tab.-3 fig. supl.-1 tab. supl.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M110.154021
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