Short-lived alpha-helical intermediates in the folding of beta-sheet proteins.
Several lines of evidence point strongly toward the importance of highly alpha-helical intermediates in the folding of all globular proteins, regardless of their native structure. However, experimental refolding studies demonstrate no observable alpha-helical intermediate during refolding of some beta-sheet proteins and have dampened enthusiasm for this model of protein folding. In this study, beta-sheet proteins were hypothesized to have potential to form amphiphilic helices at a period of <3.6 residues/turn that matches or exceeds the potential at 3.6 residues/turn. Hypothetically, such potential is the basis for an effective and unidirectional mechanism by which highly alpha-helical intermediates might be rapidly disassembled during folding and potentially accounts for the difficulty in detecting highly alpha-helical intermediates during the folding of some proteins. The presence of this potential was confirmed, indicating that a model entailing ubiquitous formation of alpha-helical intermediates during the folding of globular proteins predicts previously unrecognized features of primary structure. Further, the folding of fatty acid binding protein, a predominantly beta-sheet protein that exhibits no apparent highly alpha-helical intermediate during folding, was dramatically accelerated by 2,2,2-trifluoroethanol, a solvent that stabilizes alpha-helical structure. This observation suggests that formation of an alpha-helix can be a rate-limiting step during folding of a predominantly beta-sheet protein and further supports the role of highly alpha-helical intermediates in the folding of all globular proteins.
Chen
Eefei
E
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95060, USA.
Everett
Mary Lou
ML
Holzknecht
Zoie E
ZE
Holzknecht
Robert A
RA
Lin
Shu S
SS
Bowles
Dawn E
DE
Parker
William
W
D050556:Fatty Acid-Binding Proteins / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012997:Solvents
D050556:Fatty Acid-Binding Proteins; D012997:Solvents