title: An expanded view of the protein folding landscape of PDZ domains.
abstract: Most protein domains fold in an apparently co-operative and two-state manner with only the native and denatured states significantly populated at any experimental condition. However, the protein folding energy landscape is often rugged and different transition states may be rate limiting for the folding reaction under different conditions, as seen for the PDZ protein domain family. We have here analyzed the folding kinetics of two PDZ domains and found that a previously undetected third transition state is rate limiting under conditions that stabilize the native state relative to the denatured state. In light of these results, we have re-analyzed previous folding data on PDZ domains and present a unified folding mechanism with three distinct transition states separated by two high-energy intermediates. Our data show that sequence composition tunes the relative stabilities of folding transition states within the PDZ family, while the overall mechanism is determined by topology. This model captures the kinetic folding mechanism of all PDZ domains studied to date.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, SE-75123 Uppsala, Sweden.
authors.forename: Greta
authors.initials: G
authors.lastname: Hultqvist
authors.forename: Søren W
authors.initials: SW
authors.lastname: Pedersen
authors.forename: Celestine N
authors.initials: CN
authors.lastname: Chi
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.forename: Stefano
authors.initials: S
authors.lastname: Gianni
authors.forename: Per
authors.initials: P
authors.lastname: Jemth
mesh_terms: D007700:Kinetics; D008956:Models, Chemical; D009154:Mutation; D054731:PDZ Domains; D017510:Protein Folding