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Related Experiment Videos

Protein folding intermediates and pathways studied by hydrogen exchange.

S W Englander1

  • 1Johnson Research Foundation, Philadelphia, Pennsylvania, USA. walter@HX2.Med.upenn.Edu

Annual Review of Biophysics and Biomolecular Structure
|August 15, 2000
PubMed
Summary

Understanding protein folding requires characterizing barriers and intermediates. Hydrogen exchange methods reveal partially unfolded forms (PUFs) and distinct folding pathways, explaining varied protein folding behaviors.

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Area of Science:

  • Biochemistry
  • Structural Biology
  • Chemical Physics

Background:

  • The protein-folding problem remains a significant challenge in molecular biology.
  • Protein folding intermediates are difficult to study using traditional structural methods.
  • Understanding folding pathways is crucial for deciphering protein function and dysfunction.

Purpose of the Study:

  • To characterize the barriers that impede protein folding.
  • To identify and characterize intermediate structures involved in protein folding.
  • To elucidate the distinct folding pathways of globular proteins.

Main Methods:

  • Utilized hydrogen exchange (HX) methods to detect and characterize protein folding intermediates.
  • Employed kinetic and equilibrium modes of HX to study intermediates on various timescales.

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  • Analyzed barrier processes including nucleation-collapse, secondary structure formation, and misfolding.

    • Main Results:

    • Identified discrete, metastable, native-like partially unfolded forms (PUFs) dominating folding landscapes.
    • Characterized transient kinetic, labile equilibrium molten globule, and populated intermediates.
    • Revealed three key barrier processes: nucleation-collapse, secondary structure assembly, and error-dependent misfolding.

    Conclusions:

    • Protein folding landscapes are characterized by a few key partially unfolded forms (PUFs).
    • Stepwise unfolding and refolding of cooperative secondary structures generate distinct folding pathways.
    • Folding heterogeneity arises from misfolding and reorganization barriers, explaining diverse protein folding behaviors.