Molecular plasticity of β-catenin:: New insights from single-molecule measurements and MD simulation
Molecular plasticity of β-catenin:: New insights from single-molecule measurements and MD simulation
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DOI：
10.1110/ps.072773007
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发表时间：
2007-09-01
期刊：
影响因子：
8
通讯作者：
Horton, Michael
中科院分区：
文献类型：
--
作者：
Ritco-Vonsovici, Monica;Ababou, Abdessamad;Horton, Michael
多功能蛋白β-连环蛋白在细胞黏附中发挥重要作用，并通过Wnt信号通路控制细胞分化、发展和癌症的发生。不同的分子形式的β-连环蛋白可能构成这两种功能的基础吗？我们的单分子力谱与分子动力学(MD)模拟，提出了一个模型，在该模型中，细胞在平衡状态下产生各种形式的β-连环蛋白。我们发现β-连环蛋白和转录因子TCF4形成了两个不同亲和力的复合体。特定的细胞反应是通过配体结合到特定的匹配的预先存在的构象来实现的。我们的MD模拟表明，复合体来自蛋白质核心区的两个构象，其先前存在的分子形式可能源于β-连环蛋白主要结合部位的灵活区域的微小变化。这种产生各种形式的机制为定制未来的治疗策略提供了一条途径。
The multifunctional protein, beta-catenin, has essential roles in cell adhesion and, through the Wnt signaling pathway, in controlling cell differentiation, development, and generation of cancer. Could distinct molecular forms of beta- catenin underlie these two functions? Our single- molecule force spectroscopy of armadillo beta-catenin, with molecular dynamics ( MD) simulation, suggests a model in which the cell generates various forms of beta- catenin, in equilibrium. We find beta-catenin and the transcriptional factor Tcf4 form two complexes with different affinities. Specific cellular response is achieved by the ligand binding to a particular matching preexisting conformer. Our MD simulation indicates that complexes derive from two conformers of the core region of the protein, whose preexisting molecular forms could arise from small variations in flexible regions of the beta-catenin main binding site. This mechanism for the generation of the various forms offers a route to tailoring future therapeutic strategies.