Initial conformational changes of human transthyretin under partially denaturing conditions
Initial conformational changes of human transthyretin under partially denaturing conditions
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DOI：
10.1529/biophysj.105.059642
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发表时间：
2005-07-01
影响因子：
3.4
通讯作者：
Huo, SH
中科院分区：
文献类型：
--
作者：
Yang, MF;Lei, M;Huo, SH
人甲状腺素运载蛋白（TTR）是一种淀粉样蛋白。TTR淀粉样蛋白形成的途径已经基于证据线提出：TTR四聚体首先解离成天然单体，这被证明是原纤维形成中的限速步骤。随后，单体物质部分解折叠以形成聚集中间体。一旦形成这样的中间体，随后的自组装过程是下坡聚合。因此，解离后单体内的三级结构变化对于淀粉样蛋白的形成是必需的。这些三级结构变化可以通过部分变性来促进。为了探测部分变性条件下的构象变化，在300和350 K收集了野生型（WT）及其致病性变体的五个独立轨迹，导致模拟总计59 ns。在这些条件下，L55 P变体比野生型和V30 M变体更不稳定。我们已经观察到，WT-TTR的D链被困在两个局部最小值：天然构象和类似于L55 P变体的残基54-55的表面环的淀粉样折叠。在四聚体状态下，F链在F-F'界面处以大间隔弯曲。该链在单体状态下变得更平坦，这可以促进新的F-F'界面的形成，其具有可能延长的氢键和/或在原纤维状态下的β-链寄存器中的移位。在展开过程中，股H和G以及股H和A之间的反相关运动将H股拉出内片平面，导致内片更加扭曲。我们的模拟提供了重要的详细结构信息的部分未折叠状态的TTR，可能与淀粉样蛋白的中间体。
Human transthyretin (TTR) is an amyloidogenic protein. The pathway of TTR amyloid formation has been proposed based on lines of evidence: TTR tetramer first dissociates into native monomers, which is shown to be a rate-limiting step in the formation of fibrils. Subsequently, the monomeric species partially unfold to form the aggregation intermediates. Once such intermediates are formed, the following self-assembly process is a downhill polymerization. Hence, tertiary structural changes within the monomers after the dissociation are essential for the amyloid formation. These tertiary structural changes can be facilitated by partial denaturation. To probe the conformational changes under the partially denaturing conditions, five independent trajectories were collected for the wild-type (WT) and its pathogenic variants at 300 and 350 K, resulting in simulations that totaled 59 ns. Under these conditions, L55P variant is more labile than the wild-type and V30M variant. We have observed that the D strand of WT-TTR is trapped in two local minima: the native conformation and the amyloidogenic fold that resembles the surface loop of residues 54-55 of L55P variant. In the tetrameric state, the F strand is bent with large separations at the F-F' interface. This strand becomes flatter in the monomeric state, which may facilitate the formation of new F-F' interface with possible prolonged hydrogen bonds and/or shift in beta-strand register in the fibril state. During the unfolding process, the anticorrelated motion between the strands H and G as well as the strands H and A pulls the H strand out of the inner sheet plane, leading to a more twisted inner sheet. Our simulation has provided important detailed structural information about the partially unfolded state of TTR that may be related to the amyloidogenic intermediates.