アクティブボード・２００８年１０月
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研究発表を行った学会；
・VIIth International symposium on Familial Amyloid Polyneurophathy.
　２００８年９月２日～５日(London, UK)

タイトル；Glu54 mutations in transthyretin affect thyroxine binding and tetramer stability, resulting in aggressive familial amyloid polyneuropathy.
　
発表者；　宮田　将徳　氏
　　　（熊本大学　大学院薬学教育部　薬物動態制御学分野）
Abstract；
　Transthyretin (TTR) is a one of serum protein and act as a transporter of thyroxine hormone and retinol binding protein. Recently, a lot of studies have reported that TTR is crucial for neuronal cell growth and development. However, a point mutation of TTR contributes to several phenotype of familial amyloid polyneurophathy (FAP). In this study, we showed a first report about the mechanisms of high amyloidogenic property of Glu54 variant TTR The Glu54 variants using biochemical and crystal structural analyses. Kinetic and thermodynamic stabilities of E54G and E54K TTRs were lower than wild-type TTR. The comparison of crystal structures showed that the substitution of Glu54 altered the structure of b-strand D region because of the difference of the surface electrostatics with that of wild-type TTR. The substitution of Glu54 reduced the negative charge around the b-strand D region, resulting in an increase of positive charged area in E54G and E54K TTRs compared with wild-type TTR. Furthermore, The entrance of thyroxine (T4) binding pocket structure, which is involved in tetramer stability through binding of T4, was changed in E54G and E54K TTRs compared with wild-type TTR. Co-crystallization of TTR-T4 complexes demonstrated that the electron density map of T4 in E54G TTR is almost identical with wild-type TTR, however, that of E54K TTR is lower than wild-type TTR. In agreement with these results, T4 has little inhibitory effect on amyloid fibril formation in E54K TTR. These changes may explain why E54G and E54K TTRs display the aggressive phenotypes of FAP.