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Transthyretin quaternary and tertiary structural changes facilitate misassembly into amyloid
1Department of Chemistry, Texas A&M University, College Station 77843-3255, USA.
Advances in Protein Chemistry
|January 1, 1997
Summary
Human transthyretin (TTR) forms amyloid fibrils via a destabilized intermediate. Stabilizing TTR
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Medicine
Background:
- Human transthyretin (TTR) can misfold into amyloid fibrils.
- Amyloid formation is linked to diseases like familial amyloid polyneuropathy (FAP).
Purpose of the Study:
- To elucidate the mechanism of TTR amyloid fibril formation.
- To identify therapeutic strategies for TTR amyloid diseases.
Main Methods:
- Partial acid denaturation and sedimentation velocity methods.
- Spectroscopic methods and proteolysis sensitivity studies.
- Analysis of familial amyloid polyneuropathy (FAP) and suppressor mutations.
Main Results:
- Partial acid denaturation yields a monomeric amyloidogenic intermediate.
- FAP mutations destabilize TTR, promoting intermediate formation and amyloid assembly.
- Suppressor mutations stabilize TTR, inhibiting amyloid formation.
- Small molecules stabilize native TTR, preventing amyloidogenesis.
Conclusions:
- TTR amyloid formation involves a destabilized monomeric intermediate.
- FAP mutations favor this intermediate, while suppressor mutations disfavor it.
- Stabilizing the native TTR tetramer is a viable therapeutic strategy for amyloid disease.