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Branching in the sequential folding pathway of cytochrome c

¹ Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6059, USA

(RECEIVED April 2, 2007; FINAL REVISION May 25, 2007; ACCEPTED May 25, 2007)

Previous results indicate that the folding pathways of cytochrome c and other proteins progressively build the target native protein in a predetermined stepwise manner by the sequential formation and association of native-like foldon units. The present work used native state hydrogen exchange methods to investigate a structural anomaly in cytochrome c results that suggested the concerted folding of two segments that have little structural relationship in the native protein. The results show that the two segments, an 18-residue omega loop and a 10-residue helix, are able to unfold and refold independently, which allows a branch point in the folding pathway. The pathway that emerges assembles native-like foldon units in a linear sequential manner when prior native-like structure can template a single subsequent foldon, and optional pathway branching is seen when prior structure is able to support the folding of two different foldons.

Keywords: protein folding; foldon; partially unfolded form; sequential stabilization; predetermined pathway; cytochrome c

³ Department of Chemistry, University of Minnesota, 313 Chemistry, 1039 University Drive, Duluth, MN 55812, USA.

Reprint requests to: Mallela M.G. Krishna, Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6059, USA; e-mail: kmallela{at}mail.med.upenn.edu; fax: (215) 898-2415.

Abbreviations: Cyt c, cytochrome c; WT, wild-type Cyt c; pWT, pseudo-wild-type recombinant equine Cyt c (H26N, H33N); HX, hydrogen exchange; NHX, native state hydrogen exchange; PUF, partially unfolded form; GdmCl, guanidinium chloride; pDr, pH of D₂O solution read by glass electrode.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.072922307.

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