以核磁共振研究來理解轉運蛋白之野生型和突變型A97S的結構及動力學差異

Abstract

家族性類澱粉多發性神經病變，是一種具遺傳性的罕見疾病。它是類澱粉沉積症的一種，類澱粉蛋白會影響人體的器官與組織，尤其是心臟及神經病變。嚴重時會導致器官衰竭終至死亡，而對於此疾病目前沒有完全有效的治療方法。轉運蛋白是一種負責運輸甲狀腺素及視黃醇結合蛋白的同源四聚體蛋白，也是家族性類澱粉多發性神經病變的代表性蛋白之一。主要的途徑為此蛋白質的突變型因四聚體結構解離而形成單體，其三級結構會因錯誤折疊而形成類澱粉蛋白。在本研究中，選擇了野生型和A97S突變型進行比較，A97S是台灣病人特有的突變型。透過液態核磁共振光譜儀的分析，來進一步認識兩者之間在結構上以及蛋白質的內部動態的細微變化。發現相較於野生型，A97S突變型中，尤其是在突變的胺基酸位置附近，在蛋白質的結構上的較為明顯的不同，連帶影響到了相鄰的胺基酸。而在動態的分析上，在第97個胺基酸(點突變位置)附近也發現了較為快速的內部動態，所以我們推論出A97S突變型在構型上及內部動力學的差異所帶來影響可能為致病的因素。

Familial amyloid polyneuropathy, a rare hereditary disease, is an amyloidosis associated with the formation of protein amyloid. Currently, there is no fully effective treatment available. Protein amyloid deposits could occur in the organs and tissues of the human body, especially the heart and neuropathy. In severe cases, it leads to organ failure and death. Transthyretin is a homotetramer protein responsible for transporting thyroxine and retinol-binding protein, causing 70% of the familial amyloid polyneuropathy cases. The key process for transthyretin to form amyloid is the dissociation of the tetrameric transthyretin into monomers. The monomers can undergo misfolding process, leading to amyloid formation.In this study, I selected the wild-type and the A97S mutant which is a unique phenotype for Taiwanese TTR-FAP patients for comparison. Through the analysis of the solution-state nuclear magnetic resonance HSQC spectra and relaxation data, we can understand the structural and dynamic differences between WT and mutant transthyretin. I discovered obvious structural differences and flexible dynamic effects around the position where the mutated amino acid occurs. In conclusion, I deduce that the differences in the structure and internal dynamics of TTR protein may play an important role in determining its pathogenic factor.