Modulating conformational factors in transthyretin amyloid.

We have analysed the structure, binding properties, stability and amyloidogenicity of particular transthyretin (TTR) mutations-TTR Met30 and TTR Pro55, both associated with familial amyloid polyneuropathy, and TTR Met119, a non-pathogenic TTR mutation with apparent protective effects on the amyloidogenicity of the Met30 mutation. Our results show that in contrast to the Met30 mutation, the Met119 mutation increases the stability of the tetramer towards dissociation into monomers and confers a higher affinity to thyroxine, which binds on the channel that runs through the tetramer. This variant also shows a greater resistance to amyloid formation in vitro, in contrast to the Pro55 variant, which is more susceptible to amyloid formation. Crystallographic studies of the structure of the Pro55 variant are underway and reveal major conformational changes. Interestingly, these changes affect the D strand of TTR, which when deleted or modified in vitro leads to accelerated rates of amyloid formation. The conformational changes observed in these "aggressive' mutations may resemble intermediate forms in the process of amyloidogenesis.