Protein folding: adding a nucleus to guide helix docking reduces landscape roughness.
The elongated three-helix-bundle spectrin domains R16 and R17 fold and unfold unusually slowly over a rough energy landscape, in contrast to the homologue R15, which folds fast over a much smoother, more typical landscape. R15 folds via a nucleation-condensation mechanism that guides the docking of the A and C-helices. However, in R16 and R17, the secondary structure forms first and the two helices must then dock in the correct register. Here, we use variants of R16 and R17 to demonstrate that substitution of just five key residues is sufficient to alter the folding mechanism and reduce the landscape roughness. We suggest that, by providing access to an alternative, faster, folding route over their landscape, R16 and R17 can circumvent their slow, frustrated wild-type folding mechanism.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Beth G
BG
Wensley
Lee Gyan
LG
Kwa
Sarah L
SL
Shammas
Joseph M
JM
Rogers
Jane
J
Clarke
D019943:Amino Acid Substitution; D007700:Kinetics; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013049:Spectrin / Q000737:chemistry* / Q000235:genetics; D013816:Thermodynamics; D014783:Viscosity
D013049:Spectrin