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, Jose Rizo-Rey, John F. Hunt, Philip J Thomas

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)381-388
Number of pages8
JournalNature Structural Biology
Volume9
Issue number5
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics

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