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Related Experiment Videos

Partially folded intermediates in insulin fibrillation.

Atta Ahmad1, Ian S Millett, Sebastian Doniach

  • 1Department of Chemistry and Biochemistry, University of California, Santa Cruz 95064, USA.

Biochemistry
|October 1, 2003
PubMed
Summary

Guanidine hydrochloride (Gdn.HCl) accelerates insulin fibrillation by promoting hexamer dissociation and forming partially unfolded monomers. This understanding is crucial for therapeutic insulin stability and delivery.

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Area of Science:

  • Biochemistry
  • Protein Chemistry
  • Materials Science

Background:

  • Native insulin forms stable hexamers at neutral pH.
  • Destabilizing conditions promote insulin hexamer dissociation and amyloid fibril formation.
  • Insulin fibrillation presents challenges in therapeutic applications.

Purpose of the Study:

  • To investigate the effect of guanidine hydrochloride (Gdn.HCl) on insulin fibrillation.
  • To elucidate the structural changes and intermediates involved in insulin fibrillation.
  • To understand the mechanism of Gdn.HCl-induced acceleration of insulin fibrillation.

Main Methods:

  • Systematic investigation of insulin structural perturbations induced by Gdn.HCl.
  • Analysis of insulin dissociation states (hexamer, dimer, monomer) at varying Gdn.HCl concentrations.

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  • Correlation of fibrillation kinetics with the population of specific insulin conformations.

    • Main Results:

    • Low Gdn.HCl concentrations (0.25 M) induce hexamer dissociation into dimers.
    • Moderate Gdn.HCl concentrations lead to partially unfolded dimer and monomer states.
    • Gdn.HCl significantly accelerates insulin fibrillation, particularly via the expanded monomer intermediate.
    • Fibrillation yield decreases at high Gdn.HCl concentrations, despite accelerated kinetics.

    Conclusions:

    • Insulin fibrillation involves both changes in association state and conformational changes.
    • The expanded monomer is a key amyloidogenic intermediate.
    • Understanding these mechanisms is vital for improving insulin stability and delivery systems.