Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques: beta(2)-microglobulin amyloidosis.
Fibril modelling by sequence and structure conservation analysis combined with protein docking techniques: beta(2)-microglobulin amyloidosis.
复制标题
通过序列和结构保守分析结合蛋白质对接技术进行原纤维建模：β(2)-微球蛋白淀粉样变性。
DOI：
10.1016/j.bbapap.2005.07.012
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Nussinov,Ruth
中科院分区：
文献类型：
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作者：
Benyamini,Hadar;Gunasekaran,Kannan;Wolfson,Haim;Nussinov,Ruth
获得淀粉样蛋白原纤维的原子分辨率结构模型目前是不可能的，但对我们理解淀粉样蛋白的机制至关重要。天然球状结构域转化为淀粉样纤维的不同途径总是涉及结构域不稳定。因此，定位一个结构域的不稳定片段对于理解其淀粉样变性转化并可能控制它是重要的。Benyamini，K. Gunasekaran，H.沃尔夫森河Nussinov，Conservation and amyloid formation：a study of the gelsolin-like family，Proteins 51（2003）266-282. [24]]我们对β2-微球蛋白（β2-m）结构域进行了广泛的序列和结构保守性分析。我们的数据集包括51个属于“C1 set domain”家族的高分辨率结构和132个聚类的PSI-BLAST搜索结果。发现β2-m结构域对应于链A（残基12-18）、D（45-55）和G（91-95）的片段保守性和稳定性较低，而发现中心链B（残基22-28）、C（36-41）、E（62-70）和F（78-83）保守和稳定。我们的研究结果得到了各种实验方法的积累，包括尿素变性，有限的蛋白水解，H/D交换和NMR和X射线晶体学结构测定的观察结果的支持。我们使用我们的保守性研究结果与实验文献信息一起提出了β2-m聚合单元的结构模型。成对蛋白质对接和随后的单体以相同的方式堆积表明与交叉β结构一致的原纤维模型。
Obtaining atomic resolution structural models of amyloid fibrils is currently impossible, yet crucial for our understanding of the amyloid mechanism. Different pathways in the transformation of a native globular domain to an amyloid fibril invariably involve domain destabilization. Hence, locating the unstable segments of a domain is important for understanding its amyloidogenic transformation and possibly control it. Since relative conservation is suggested to relate to local stability [H. Benyamini, K. Gunasekaran, H. Wolfson, R. Nussinov, Conservation and amyloid formation: a study of the gelsolin-like family, Proteins 51 (2003) 266–282. [24]], we performed an extensive, sequence and structure conservation analysis of the β2-microglobulin (β2-m) domain. Our dataset include 51 high resolution structures belonging to the “C1 set domain” family and 132 clustered PSI-BLAST search results. Segments of the β2-m domain corresponding to strands A (residues 12–18), D (45–55) and G (91–95) were found to be less conserved and stable, while the central strands B (residues 22–28), C (36–41), E (62–70) and F (78–83) were found conserved and stable. Our findings are supported by accumulating observations from various experimental methods, including urea denaturation, limited proteolysis, H/D exchange and structure determination by both NMR and X-ray crystallography. We used our conservation findings together with experimental literature information to suggest a structural model for the polymerized unit of β2-m. Pairwise protein docking and subsequent monomer stacking in the same manner suggest a fibril model consistent with the cross-β structure.