Abstract
The linear sequence of amino acids contains all the necessary information for a protein to fold into its unique three-dimensional structure. Native protein sequences are known to accomplish this by promoting the formation of stable, kinetically accessible structures. Here we describe a Pro residue in the center of the third transmembrane helix of the cystic fibrosis transmembrane conductance regulator that promotes folding by a distinct mechanism: disfavoring the formation of a misfolded structure. The generality of this mechanism is supported by genome-wide transmembrane sequence analyses. Furthermore, the results provide an explanation for the increased frequency of Pro residues in transmembrane α-helices. Incorporation by nature of such 'negative folding determinants', aimed at preventing the formation of off-pathway structures, represents an additional mechanism by which folding information is encoded within the evolved sequences of proteins.
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Acknowledgements
We thank members of the Thomas and Rizo laboratories for valuable discussions, S. Madden and B. Riek for expert technical assistance, B. Rost for prediction of TM α-helices, and L. Gierasch, D. Hilgemann, E. Ross, B. Goldsmith, R. Ranganathan, S. Muallem and S. Sprang for helpful comments. This work was supported by research grants from the Cystic Fibrosis Foundation and the National Institutes of Health-NIDDK to P.J.T. P.H.T is supported by an NIH predoctoral training grant. M.J.C. is the recipient of a CF Foundation fellowship. P.J.T. is an Established Investigator of the American Heart Association.
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Wigley, W., Corboy, M., Cutler, T. et al. A protein sequence that can encode native structure by disfavoring alternate conformations. Nat Struct Mol Biol 9, 381–388 (2002). https://doi.org/10.1038/nsb784
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DOI: https://doi.org/10.1038/nsb784
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