β2-microglobulin amyloidosis:: Insights from conservation analysis and fibril modelling by protein docking techniques
β2-microglobulin amyloidosis:: Insights from conservation analysis and fibril modelling by protein docking techniques
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DOI：
10.1016/s0022-2836(03)00557-6
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发表时间：
2003-06-27
影响因子：
5.6
通讯作者：
Nussinov, R
中科院分区：
文献类型：
--
作者：
Benyamini, H;Gunasekaran, K;Nussinov, R
目前的数据表明，球状结构域可能通过不同的机制形成淀粉样蛋白。然而，有迹象表明，该过程的起始总是发生在蛋白质结构域的不太稳定的片段中。我们研究了透析相关淀粉样变性中β 2-微球蛋白沉积到纤维中的序列和结构保守性。该数据集包括51个抗体恒定结构域样蛋白（Cl）的高分辨率非冗余结构和132个相关序列。我们描述了一组30个保守残基。其中23个是结构保守的，16个是序列保守的，9个是序列和结构都保守的。链A（12-18）、G（91-95）和D（45-55）是该结构域的保守性较低且稳定的区段，而链B（22-28）、C（36-41）、E（62-70）和F（78-83）是保守且稳定的区段。我们发现，保守的残基形成一个集群与网络的相互作用。所观察到的模式的保护是一致的实验数据，包括H/D交换，尿素变性和有限的蛋白水解，这表明链A和G不参与淀粉样蛋白原纤维。此外，链D的低保守性与观察结果一致，即该链可能获得不同的构象，如在结合和分离的β（2）-微球蛋白的晶体结构中所见。我们使用对接技术提出了一个模型，通过堆叠β（2）-微球蛋白单体的原纤维。我们的分析表明，有利于原纤维伸长的单体结构单元是分离的β（2）-微球蛋白的构象，没有D链上的β-凸起，也没有A和G链参与原纤维β-折叠结构。这种单体保留了所有保守的残基及其相互作用网络，增加了其在溶液中存在的可能性。两个（单体）结构单元之间的链间相互作用形成新的连续β-片层，使得单体的添加导致具有特征性交叉β结构的原纤维模型。(C)2003爱思唯尔科技有限公司。保留所有权利。
Current data suggest that globular domains may form amyloids via different mechanisms. Nevertheless, there are indications that the initiation of the process takes place invariably in the less stable segments of a protein domain. We have studied the sequence and structural conservation of beta(2)-microglobulin that deposits into fibrils in dialysis-related amyloidosis. The dataset includes 51 high-resolution non-redundant structures of the antibody constant domain-like proteins (Cl) and 132 related sequences. We describe a set of 30 conserved residues. Among them, 23 are conserved structurally, 16 are conserved sequentially and nine are conserved both sequentially and structurally. Strands A (12-18), G (91-95) and D (45-55) are the less conserved and stable segments of the domain, while strands B (22-28), C (36-41), E (62-70) and F (78-83) are the conserved and stable segments. We find that the conserved residues form a cluster with a network of interactions. The observed pattern of conservation is consistent with experimental data including H/D exchange, urea denaturation and limited proteolysis that suggest that strands A and G do not participate in the amyloid fibril. Additionally, the low conservation of strand D is consistent with the observation that this strand may acquire different conformations as seen m crystal structures of bound and isolated beta(2)-microglobulin. We used a docking technique to suggest a model for a fibril via stacking Of beta(2)-microglobulin monomers. Our analysis suggests that the favored monomer building block for fibril elongation is the conformation of the isolated beta(2)-microglobulin, without the beta-bulge on strand D and without strands A and G participating in the fibril beta-sheet structure. This monomer retains all the conserved residues and their network of interactions, increasing the likelihood of its existence in solution. The inter-strand interaction between the two (monomer) building blocks forms a new continuous beta-sheet such that addition of monomers results in a fibril model that has the characteristic cross-beta structure. (C) 2003 Elsevier Science Ltd. All rights reserved .