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A protein sequence that can encode native structure by disfavoring alternate conformations.

W Christian Wigley·Michael J Corboy·Todd D Cutler·Patrick H Thibodeau·Jorge Oldan·Min Goo Lee·Josep Rizo·John F Hunt·Philip J Thomas
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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 alpha-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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Amino Acid SequenceBenzothiazolesCell LineCell MembraneCircular DichroismComputational BiologyCystic Fibrosis Transmembrane Conductance RegulatorGenomeHumansLiposomesMicellesMolecular Sequence DataMutationProlineProtein FoldingProtein Structure, SecondaryRecombinant Fusion ProteinsSpectroscopy, Fourier Transform InfraredStructure-Activity RelationshipThermodynamicsThiazolesJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

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W Christian Wigley, Michael J Corboy, Todd D Cutler, Patrick H Thibodeau, Jorge Oldan, Min Goo Lee, Josep Rizo, John F Hunt, Philip J Thomas. 2002. A protein sequence that can encode native structure by disfavoring alternate conformations.. https://doi.org/10.1038/nsb784

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