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

Nat Struct Biol. 2002 May;9(5):381-8. doi: 10.1038/nsb784.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Benzothiazoles
  • Cell Line
  • Cell Membrane / metabolism
  • Circular Dichroism
  • Computational Biology
  • Cystic Fibrosis Transmembrane Conductance Regulator / chemistry*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Genome
  • Humans
  • Liposomes / metabolism
  • Micelles
  • Molecular Sequence Data
  • Mutation / genetics
  • Proline / genetics
  • Proline / metabolism*
  • Protein Folding*
  • Protein Structure, Secondary
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Spectroscopy, Fourier Transform Infrared
  • Structure-Activity Relationship
  • Thermodynamics
  • Thiazoles / metabolism


  • Benzothiazoles
  • CFTR protein, human
  • Liposomes
  • Micelles
  • Recombinant Fusion Proteins
  • Thiazoles
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • thioflavin T
  • Proline