Sebastião M P, Lamzin V, Saraiva M J, Damas A M
Unidade de Estrutura Molecular and
J Mol Biol. 2001 Mar 2;306(4):733-44. doi: 10.1006/jmbi.2000.4415.
Transthyretin (TTR) amyloidosis is a conformational disturbance, which, like other amyloidoses, represents a life threat. Here, we report a TTR variant, TTR Thr119Met, that has been shown to have a protective role in the development of clinical symptoms in carriers of TTR Val30Met, one of the most frequent variants among TTR amyloidosis patients. In order to understand this effect, we have determined the structures of the TTR Val30Met/Thr119Met double mutant isolated from the serum of one patient and of both the native and thyroxine complex of TTR Thr119Met. Major conclusions are: (i) new H-bonds within each monomer and monomer-monomer inter-subunit contacts, e.g. Ser117-Ser117 and Met119-Tyr114, increase protein stability, possibly leading to the protective effect of the TTR Val30Met/Thr119Met variant when compared to the single variant TTR Val30Met. (ii) The mutated residue (Met119) extends across the thyroxine binding channel inducing conformational changes that lead to closer contacts between different dimers within the tetramer. The data, at atomic resolution, were essential to detect, for the first time, the subtle changes in the inter-subunit contacts of TTR, and explain the non-amyloidogenic potential of the TTR Thr119Met variant, improving considerably current research on the TTR amyloid fibril formation pathway.
转甲状腺素蛋白（TTR）淀粉样变性是一种构象紊乱疾病，与其他淀粉样变性一样，对生命构成威胁。在此，我们报告一种TTR变体，即TTR Thr119Met，已证明它对TTR Val30Met携带者临床症状的发展具有保护作用，TTR Val30Met是TTR淀粉样变性患者中最常见的变体之一。为了解这种作用，我们测定了从一名患者血清中分离出的TTR Val30Met/Thr119Met双突变体以及TTR Thr119Met的天然形式和甲状腺素复合物的结构。主要结论如下：（i）每个单体内部新形成的氢键以及单体 - 单体亚基间的接触，例如Ser117 - Ser117和Met119 - Tyr114，增加了蛋白质稳定性，与单一变体TTR Val30Met相比，这可能导致TTR Val30Met/Thr119Met变体产生保护作用。（ii）突变残基（Met119）延伸穿过甲状腺素结合通道，引发构象变化，导致四聚体内不同二聚体之间的接触更紧密。这些原子分辨率的数据对于首次检测TTR亚基间接触的细微变化至关重要，并解释了TTR Thr119Met变体的非淀粉样变性潜力，极大地推动了当前关于TTR淀粉样纤维形成途径的研究。
