The amyloidogenic potential of transthyretin variants correlates with their tendency to aggregate in solution

FEBS Letters

Quintas, Alexandre²  Saraiva, M.J.M³  Brito, Rui M.M¹ 

[1] Centro de Neurociências de Coimbra, Universidade de Coimbra, 3000 Coimbra, Portugal;Instituto Superior de Ciências da Saúde Sul, 2825 Monte da Caparica, Portugal;Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto, 4050 Porto, Portugal

关键词: Transthyretin;    Amyloid;    Amyloidosis;    Amyloidogenesis;    Familial amyloidotic polyneuropathy;    Protein stability;    Gel filtration chromatography;    TTR;    transthyretin;    V30M-TTR;    transthyretin with valine at position 30 replaced by a methionine;    L55P-TTR;    transthyretin with leucine at position 55 replaced by a proline;    T119M-TTR;    transthyretin with threonine at position 119 replaced by a methionine;    WT;    wild type;    Tris;    tris(hydroxymethyl)aminomethane;   

DOI  :  10.1016/S0014-5793(97)01398-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Amyloid fibril formation and deposition are the basis for a wide range of diseases, including spongiform encephalopathies, Alzheimer's and familial amyloidotic polyneuropathies. However, the molecular mechanisms of amyloid formation are still poorly characterised. In certain forms of familial amyloidotic polyneuropathy (FAP), the amyloid fibrils are mostly constituted by variants of transthyretin (TTR). V30M-TTR is the most frequent variant, and L55P-TTR is the variant associated with the most aggressive form of amyloidosis. Here, we report gel filtration chromatography experiments to characterise the aggregation states of WT-, V30M-, L55P-TTR and a non-amyloidogenic variant, T119M-TTR, in solution, at nearly physiological pH. These studies show that all four protein tetramers dissociate to monomer upon dilution, in the sub-micromolar range, at pH 7.0. The amyloidogenic proteins V30M- and L55P-TTR show a complex equilibrium between monomers, tetramers and high molecular weight aggregate species. These aggregates dissociate directly to monomer upon dilution. This study shows that the tendency to form aggregates among the four studied proteins correlates with their known amyloidogenic potential. Thus, the amyloidogenic mutations could perturb the structure and/or stability of the monomeric species leading initially to the formation of soluble aggregates and at a later stage to insoluble amyloid fibrils.

【 授权许可】

Unknown