A protein sequence that can encode native structure by disfavoring alternate conformations.
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.
Wigley
W Christian
WC
Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9040, USA.
Corboy
Michael J
MJ
Cutler
Todd D
TD
Thibodeau
Patrick H
PH
Oldan
Jorge
J
Lee
Min Goo
MG
Rizo
Josep
J
Hunt
John F
JF
Thomas
Philip J
PJ
D000595:Amino Acid Sequence; D052160:Benzothiazoles; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D019295:Computational Biology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016678:Genome; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D008823:Micelles; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011392:Proline / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013844:Thiazoles / Q000378:metabolism
D052160:Benzothiazoles; C505032:CFTR protein, human; D008081:Liposomes; D008823:Micelles; D011993:Recombinant Fusion Proteins; D013844:Thiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C009462:thioflavin T; D011392:Proline