Conformational detours during folding of a collapsed state

TY - JOUR

T1 - Conformational detours during folding of a collapsed state

AU - Otzen, Daniel E.

PY - 2005/6/30

Y1 - 2005/6/30

N2 - The protein S6 is a useful model to probe the role of partially folded states in the folding process. In the absence of salt, S6 folds from the denatured state D to the native state N without detectable intermediates. High concentrations of sodium sulfate induce the accumulation of a collapsed state C, which is off the direct folding route. However, the mutation VA85 enables S6 to fold from C directly to N through the transition state TSC. According to the denaturant dependence of this reaction, TSC and C are equally compact, but the data are difficult to deconvolute. Therefore, I have measured the heat capacities (ΔCp) for the D→C and C→TSC transitions. The ΔCp-values suggest that C needs to increase its surface area in order to fold directly to N. This underlines that it is a misfolded state that can only fold by at least partial unfolding. In contrast to the C-state formed by S6 wildtype, the VA85 C-state is just as compact as the native state, and this may be a prerequisite for direct folding. Individual "gatekeeper" residues may thus play a disproportionately large role in guiding proteins through different folding pathways.

AB - The protein S6 is a useful model to probe the role of partially folded states in the folding process. In the absence of salt, S6 folds from the denatured state D to the native state N without detectable intermediates. High concentrations of sodium sulfate induce the accumulation of a collapsed state C, which is off the direct folding route. However, the mutation VA85 enables S6 to fold from C directly to N through the transition state TSC. According to the denaturant dependence of this reaction, TSC and C are equally compact, but the data are difficult to deconvolute. Therefore, I have measured the heat capacities (ΔCp) for the D→C and C→TSC transitions. The ΔCp-values suggest that C needs to increase its surface area in order to fold directly to N. This underlines that it is a misfolded state that can only fold by at least partial unfolding. In contrast to the C-state formed by S6 wildtype, the VA85 C-state is just as compact as the native state, and this may be a prerequisite for direct folding. Individual "gatekeeper" residues may thus play a disproportionately large role in guiding proteins through different folding pathways.

KW - Detour

KW - Energy landscape

KW - Heat capacity

KW - Intermediate

KW - Misfolded state

KW - Protein folding

UR - http://www.scopus.com/inward/record.url?scp=20644450354&partnerID=8YFLogxK

U2 - 10.1016/j.bbapap.2005.05.006

DO - 10.1016/j.bbapap.2005.05.006

M3 - Journal article

C2 - 15955750

AN - SCOPUS:20644450354

SN - 1570-9639

VL - 1750

SP - 146

EP - 153

JO - Biochimica et Biophysica Acta - Proteins and Proteomics

JF - Biochimica et Biophysica Acta - Proteins and Proteomics

IS - 2

ER -