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Kinetic and Conformational Insights into Islet Amyloid Polypeptide Self-Assembly Using a Biarsenical Fluorogenic
Noé Quittot1, Mathew Sebastiao1, Soultan Al-Halifa1
1Department of Chemistry, Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, University of Québec in Montreal , C.P. 8888, Succursale Centre-Ville, Montreal, Québec H3C 3P8, Canada.
Bioconjugate Chemistry
|January 24, 2018
Summary
Researchers used a novel fluorescein arsenical hairpin (FlAsH) probe method to study islet amyloid polypeptide (IAPP) self-assembly. This technique provides new insights into toxic prefibrillar intermediate formation in amyloid diseases like type II diabetes.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- Amyloid fibril formation is linked to various diseases, with toxic prefibrillar intermediates driving pathology.
- Understanding the formation and conformation of these intermediates is crucial but challenging due to their transient nature.
Purpose of the Study:
- To adapt and apply the fluorescein arsenical hairpin (FlAsH) probe method for studying islet amyloid polypeptide (IAPP) self-assembly.
- To gain kinetic and conformational insights into the amyloidogenic pathway of IAPP.
Main Methods:
- Utilized the FlAsH probe, which binds to tetracysteine motifs, to detect IAPP oligomerization.
- Employed positional scanning of the Cys-Cys motif to evaluate FlAsH-binding site stability during self-assembly.
- Characterized conformational changes in IAPP monomers and oligomers.
Main Results:
- Demonstrated rapid monomer self-recognition via C-terminal domain convergence.
- Observed N-terminal domain proximity only upon cross-β-sheet amyloid structure formation.
- Showed the FlAsH method can detect thioflavin T-negative fibrils and screen inhibitors.
Conclusions:
- The FlAsH detection method, with positional scanning of the split-tetracysteine motif, offers unique time-dependent conformational insights into amyloidogenic pathways.
- This approach is valuable for studying IAPP self-assembly and identifying potential therapeutic interventions for amyloid-related diseases.
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