The mechanism by which a linear sequence of amino acids controls the folding of a protein into its unique three-dimensional structure remains incompletely understood. In the April 8 online edition Nature Structural Biology, Christian Wigley and colleagues from University of Texas Southwestern Medical Center, Dallas, show that a protein sequence can encode the native structure by preventing the formation of a misfolded structure.

Wigley et al. observed that a proline residue in the center of the third transmembrane helix of the cystic fibrosis transmembrane conductance regulator promotes correct folding by disfavoring alternate conformations. A genome-wide sequence analysis of transmembrane domains revealed a correlation between certain residues and proline, supporting the idea that this mechanism is a general one (Nat Struct Biol 2002, DOI: 10.1038/nsb784).

"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", concluded the authors.

1. [http://www.nature.com/nsb/ ] webcite

   Wigley WC, Corboy MJ, Cutler TD, Thibodeau PH, Oldan J, Lee MG, Rizo J, Hunt JF, Thomas PJ: A protein sequence that can encode native structure by disfavoring alternate conformations. Nat Struct Biol 2002, DOI: 10.1038/nsb784.

2. [http://www3.utsouthwestern.edu/ ] webcite

   University of Texas Southwestern Medical Center