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Ligand exchange during cytochrome c folding

S R Yeh1, S Takahashi, B Fan

  • 1Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Nature Structural Biology
|January 1, 1997
PubMed
Summary

Cytochrome c folding occurs rapidly, with a misfolded state forming and then escaping via a kinetic trap. Lowering pH reduces misfolded state formation by protonating key histidine residues.

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Area of Science:

  • Biochemistry
  • Protein Folding Dynamics
  • Biophysical Chemistry

Background:

  • Cytochrome c is a crucial protein involved in electron transport.
  • Understanding its rapid folding mechanism is vital for comprehending protein dynamics.
  • Ligand exchange and coordination states play a key role in protein function.

Purpose of the Study:

  • To investigate the submillisecond folding pathway of cytochrome c.
  • To elucidate the role of histidine residues and pH in ligand exchange.
  • To characterize the kinetics and thermodynamics of misfolded state formation and escape.

Main Methods:

  • Utilized submillisecond mixing techniques to observe rapid folding events.
  • Analyzed ligand exchange kinetics involving histidine (His) and methionine (Met) residues.
  • Measured activation energy barriers for transitions between different coordination states using pH-dependent studies.

Main Results:

  • A nascent phase of cytochrome c folding appears within 100 microseconds.
  • Ligand exchange involves inter-conversion of His 26/33, water, and Met 80 as haem ligands.
  • Misfolded histidine-histidine (HH) state formation rate decreases significantly with decreasing pH due to His protonation.
  • Activation energy barriers for transitions to histidine-methionine (HW) and HH states were determined.
  • A kinetic trapping effect was observed for the misfolded HH state, with a measured escape barrier.

Conclusions:

  • Submillisecond folding of cytochrome c involves rapid ligand exchange and potential misfolded state formation.
  • pH-dependent protonation of His 26/33 effectively suppresses the formation of the misfolded HH state.
  • The misfolded HH state acts as a kinetically trapped intermediate, influencing the overall folding pathway.

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