Acidic pH-induced conformational changes in amyloidogenic mutant transthyretin
Acidic pH-induced conformational changes in amyloidogenic mutant transthyretin
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DOI：
10.1016/j.jmb.2006.11.076
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发表时间：
2007-02-23
影响因子：
5.6
通讯作者：
Zanotti, Giuseppe
中科院分区：
文献类型：
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作者：
Pasquato, Nicola;Berni, Rodolfo;Zanotti, Giuseppe
几种蛋白质，包括转甲状腺素（TTR），可以在组织中以原纤维的形式产生细胞外不溶性聚集体，这与被称为淀粉样变性的病理状态有关。迄今为止，已有超过80种不同的TTR点突变与人类遗传性淀粉样变性有关。在体外，已知人类TTR的淀粉样原纤维的形成是由酸性ph触发的。我们在这里表明，在体外，天然的淀粉样原纤维I84S和非天然的I84A TTR突变形式在酸性培养基中产生原纤维的倾向明显高于野生型TTR。这两种突变体都在中性和酸性pH下结晶，它们的中性pH晶体结构与野生型TTR非常相似，这与之前的证据一致，表明淀粉样变性突变只会引起轻微的结构变化。相反，在中等低pH值（4.6）下，它们的晶体结构与中性pH结构相比，表现出显著的构象差异。值得注意的是，在低ph下结晶的野生型TTR中不会引起这种变化。最相关的变化包括TTR短a-螺旋的解绕以及连接α -螺旋和β -链f的环的构象变化。只有晶体二聚体的一个单体受到影响，导致四聚体对称性的破坏。这种不对称性和TTR四聚体四元结构的不稳定可能是导致两种TTR突变体在低ph下具有淀粉样变性的原因。版权所有。
DSeveral proteins, including transthyretin (TTR), can generate in tissues extracellular insoluble aggregates, in the form of fibrils, that are associated with pathological states known as amyloidoses. To date, more than 80 different TTR point mutations have been associated with hereditary amyloidosis in humans. In vitro, the formation of amyloid fibrils by human TTR is known to be triggered by acidic pH. We show here that, in vitro, the natural amyloidogenic I84S and the non-natural I84A TTR mutant forms exhibit a propensity to produce fibrils in an acidic medium significantly higher than that of wild-type TTR. The two mutant forms have been crystallized at both neutral and acidic pH. Their neutral pH crystal structures are very similar to that of wild-type TTR, consistent with previous evidence indicating that only minor structural changes are induced by amyloidogenic mutations. On the contrary, their crystal structures at moderately low pH (4.6) show significant conformational differences as compared to their neutral pH structures. Remarkably, such changes are not induced in wild-type TTR crystallized at low pH. The most relevant consist of the unwinding of the TTR short a-helix and of the change in conformation of the loop connecting the alpha-helix to beta-strand F. Only one monomer of the crystallographic dimer is affected, causing a disruption of the tetrameric symmetry. This asymmetry and a possible destabilization of the tetrameric quaternary structure of TTR may be responsible for the amyloidogenic potential of the two TTR mutant forms at low pH. (c) 2006 Elsevier Ltd. All rights reserved.