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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Benzothiazoles
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Cell Line
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Cell Membrane / metabolism
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Circular Dichroism
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Computational Biology
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Cystic Fibrosis Transmembrane Conductance Regulator / chemistry*
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Cystic Fibrosis Transmembrane Conductance Regulator / genetics
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Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
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Genome
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Humans
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Liposomes / metabolism
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Micelles
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Molecular Sequence Data
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Mutation / genetics
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Proline / genetics
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Proline / metabolism*
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Protein Folding*
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Protein Structure, Secondary
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Spectroscopy, Fourier Transform Infrared
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Structure-Activity Relationship
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Thermodynamics
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Thiazoles / metabolism
Substances
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Benzothiazoles
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CFTR protein, human
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Liposomes
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Micelles
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Recombinant Fusion Proteins
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Thiazoles
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Cystic Fibrosis Transmembrane Conductance Regulator
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thioflavin T
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Proline