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Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Protein folding: independent unrelated pathways or predetermined pathway with optional errors
Sabrina Bédard1, Mallela M G Krishna, Leland Mayne
1Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA. bedard@mail.med.upenn.edu
Summary
Protein folding kinetics are often explained by multiple pathways. This study reveals that staphylococcal nuclease folding follows a single pathway with optional errors, challenging the independent unrelated pathways model.
Area of Science:
- Biochemistry and Molecular Biology
- Protein Dynamics and Folding
- Structural Biology
Background:
- Heterogeneous protein folding kinetics are commonly modeled using independent unrelated pathways (IUP).
- This interpretation is prevalent in both experimental and theoretical protein folding studies.
- Recent structural data on folding intermediates suggest a more unified folding process.
Purpose of the Study:
- To re-evaluate the folding mechanism of staphylococcal nuclease (SNase).
- To determine if heterogeneous folding kinetics necessitate multiple parallel pathways.
- To compare the independent unrelated pathways (IUP) model with a predetermined pathway-optional error (PPOE) model.
Main Methods:
- Analysis of structural, kinetic, and thermodynamic data for SNase folding intermediates.
- Computational modeling to fit SNase folding kinetics.
- Comparison of experimental data with predictions from IUP and PPOE models.
Main Results:
- SNase folding kinetics can be accurately described by a single predetermined pathway with optional misfolding errors (PPOE model).
- The observed heterogeneity in SNase folding does not require the existence of alternative parallel pathways.
- Structural and kinetic data for various proteins align with the PPOE model, not the IUP model.
Conclusions:
- The independent unrelated pathways (IUP) model is not essential for explaining heterogeneous protein folding kinetics.
- The predetermined pathway-optional error (PPOE) model provides a more consistent explanation for observed protein folding phenomena.
- This finding has significant implications for understanding protein folding mechanisms and potential misfolding events.
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