Molecular determinants of a native-state prolyl isomerization
Roman P Jakob1, Franz X Schmid
1Laboratorium für Biochemie und Bayreuther Zentrum für Molekulare Biowissenschaften, Universität Bayreuth, D-95440 Bayreuth, Germany.
Journal of Molecular Biology
|February 24, 2009
Summary
Prolyl isomerization is key to protein folding, acting as molecular switches. Energy from beta sheet formation in phage fd gene-3 protein N2 domain shifts the Pro161 cis/trans equilibrium during folding.
Area of Science:
- Protein folding dynamics
- Biophysics
- Molecular biology
Background:
- Prolyl cis/trans isomerization is a rate-limiting step in protein folding.
- This isomerization can function as a molecular switch or timer.
- Understanding the energetic linkage between protein conformation and isomerization is crucial.
Purpose of the Study:
- To investigate the energetic linkage between protein folding and prolyl isomerization.
- To identify the structural origin of energy transfer to Pro161 in the N2 domain of phage fd gene-3 protein.
- To elucidate the molecular pathway for this energy transfer during protein refolding.
Main Methods:
- Utilized the N2 domain of phage fd gene-3 protein.
- Employed single- and double-mixing kinetic experiments.
- Conducted mutational analysis to probe structural contributions.
Main Results:
- A 10 kJ mol(-1) conformational energy release drives a 75-fold shift in the Pro161 cis/trans equilibrium during refolding.
- The energy originates primarily from the two-stranded beta sheet at the base of the Pro161 hairpin.
- Stabilization of the beta sheet when Pro161 is cis propagates energy to the isomerization site via folded connector peptides.
Conclusions:
- The beta sheet structure provides the energy to shift the Pro161 isomerization equilibrium.
- Local unfolding of connector peptides in the presence of trans-Pro161 uncouples Pro161 from the beta sheet.
- Interplay between local folding and prolyl isomerization may regulate protein communication pathways.
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