Structure of Val122Ile variant transthyretin - A cardiomyopathic mutant
Structure of Val122Ile variant transthyretin - A cardiomyopathic mutant
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DOI：
10.1107/s0907444996003307
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发表时间：
1996-09-01
期刊：
影响因子：
--
通讯作者：
Saraiva, MJ
中科院分区：
文献类型：
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作者：
Damas, AM;Ribeiro, S;Saraiva, MJ
Val 122 Ile突变型甲状腺素运载蛋白（TTR Ile 122）是一种淀粉样蛋白生成蛋白，其被描述为从患有家族性淀粉样心肌病（FAG）的患者分离的淀粉样原纤维的主要蛋白组分，所述家族性淀粉样心肌病是一种以心力衰竭和心脏中淀粉样蛋白沉积为特征的疾病。TTR沉积的原因仍然未知，可以想象，由突变引起的构象改变是淀粉样蛋白形成的基础。确定TTR Ile 122的三维结构，并在1.9埃分辨率下将其细化至15.8%的晶体学R因子。均方根键距与理想值的偏差为0.019埃，角键距与理想值的偏差为0.027埃。在不对称单元中存在两个晶体学上独立的单体允许估计原子坐标误差的额外手段。突变体的结构与野生型甲状腺素运载蛋白（TTR）的结构基本相同。最大的偏差发生在表面回路和替代区域。蛋白质是由相同的亚基组成的四聚体;每个单体具有两个四链β-片层，当两个单体通过氢键缔合形成二聚体时，所述四链β-片层延伸为八链β-片层，所述二聚体是晶体学不对称单元。缬氨酸取代异亮氨酸引入了与野生型蛋白质相关的非常小的改变;然而，它们似乎证实了不太稳定的四聚体结构的趋势。这将支持四聚体结构可能在淀粉样纤维中被破坏的观点。
The Val122Ile mutant transthyretin (TTR Ile 122) is an amyloidogenic protein which has been described as the major protein component of amyloid fibrils isolated from patients with familial amyloidotic cardiomyopathy (FAG), a disease characterized by cardiac failure and amyloid deposits in the heart. The reasons for the deposition of TTR are still unknown and it is conceivable that a conformational alteration, resulting from the mutation, is fundamental for amyloid formation. The three-dimensional structure of TTR Ile 122 was determined and refined to a crystallographic R factor of 15.8% at 1.9 Angstrom resolution. The r.m.s. deviation from ideality in bond distances is 0.019 Angstrom and in angle-bonded distances is 0.027 Angstrom. The presence of two crystallographically independent monomers in the asymmetric unit allowed additional means of estimation of atomic coordinate error. The structure of the mutant is essentially identical to that of the wild-type transthyretin (TTR). The largest deviations occur in surface loops and in the region of the substitution. The protein is a tetramer composed of identical subunits; each monomer has two four-stranded beta-sheets which are extended to eight-stranded beta-sheets when two monomers associate through hydrogen bonds forming a dimer, which is the crystallographic asymmetric unit. The replacement of valine for isoleucine introduces very small alterations in relation to the wild-type protein; nevertheless they seem to confirm a tendency for a less stable tetrameric structure. This would support the idea that the tetrameric structure might be disrupted in amyloid fibrils.