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Modulating conformational factors in transthyretin amyloid
M J Saraiva1, M R Almeida, I L Alves
1Centro de Estudos de Paramiloidose, Hospital de Sto. Antonio, Porto, Portugal.
Ciba Foundation Symposium
|January 1, 1996
Summary
Transthyretin (TTR) mutations affect amyloid formation. Met119 stabilizes TTR and resists amyloidogenesis, while Pro55 is more susceptible, offering insights into familial amyloid polyneuropathy.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Familial amyloid polyneuropathy (FAP) is linked to transthyretin (TTR) mutations.
- Understanding TTR mutation effects on stability and amyloidogenicity is crucial for FAP research.
Purpose of the Study:
- To analyze the structural, binding, stability, and amyloidogenicity properties of TTR Met30, TTR Pro55, and TTR Met119 mutations.
- To investigate the protective effects of TTR Met119 on TTR Met30-associated amyloidogenicity.
Main Methods:
- Analysis of TTR mutation structures and binding properties.
- Assessment of TTR tetramer stability and thyroxine binding affinity.
- In vitro amyloid formation assays.
- Crystallographic studies of TTR variants.
Main Results:
- TTR Met119 increases tetramer stability and thyroxine binding affinity, showing resistance to amyloid formation.
- TTR Pro55 is more susceptible to amyloid formation, with conformational changes affecting the D strand.
- Conformational changes in aggressive mutations may mimic amyloidogenesis intermediates.
Conclusions:
- TTR Met119 exhibits protective effects against amyloidogenesis, unlike pathogenic mutations like TTR Pro55.
- Structural insights into TTR mutations provide a basis for understanding familial amyloid polyneuropathy pathogenesis.