Solution structure and backbone dynamics of the TGFβ type II receptor extracellular domain
Solution structure and backbone dynamics of the TGFβ type II receptor extracellular domain
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DOI：
10.1021/bi034366a
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发表时间：
2003-09-02
期刊：
影响因子：
2.9
通讯作者：
Hinck, AP
中科院分区：
文献类型：
--
作者：
Deep, S;Walker, KP;Hinck, AP
转化生长因子β（TGF β）的同种型是25 kDa的同源二聚体多肽，其通过结合并将两种相关的、功能上不同的细胞表面受体（命名为TbetaR 1和TbetaR 2）结合在一起而发出信号。在这里，我们报告的解决方案结构的13.8 kDa的细胞外结构域的人TbetaR 2（ECTbetaR 2）计算（NN-HN），C-α-H-α，和C-α-C-O残留偶极耦合约束结合NOE距离，二面角，和标量耦合约束。比较游离的ecTbetaR 2溶液结构与TGF β 3结合的ecTbetaR 2晶体结构，揭示了骨架构象，其在规则二级结构区域上的RSD为1.0埃，总体RSD为1.4埃。结构上的差异主要落在环区，这些环区要么由可用的NMR数据定义不好，要么涉及晶体接触。游离形式的NMR结构和TGF β结合形式的晶体结构之间的所述相似性也与紧密对应一致，与TGF β 3结合的ecTbetaR 2的晶体结构相比，游离ecTbetaR 2的晶体结构的二级结构区域的RMSD为0.16埃，总体RMSD为0.51埃。尽管游离和结合形式之间存在明显的相似性，但在涉及受体界面接触区域的结构上似乎存在微小但显著的差异。骨架N-15弛豫时间的测量和解释这些由无模型的形式主义与轴向扩散各向异性进一步揭示了显着的ms到μ s的时间尺度运动集中在两个保守的二硫键和几个残基，包括TGF β结合表面。总之，这些观察结果表明，结合可能通过具有诱导适应特征的小组分的机制发生，由此受体内的柔性促进向TGF β结合状态的转变。
Isoforms of transforming growth factor beta (TGFbeta) are 25 kDa homodimeric polypeptides that signal by binding and bringing together two related, functionally distinct cell surface receptors designated as TbetaR1 and TbetaR2. Here, we report the solution structure of the 13.8 kDa extracellular domain of human TbetaR2 (ecTbetaR2) as calculated from (NN-HN), C-alpha-H-alpha, and C-alpha-C-O residual dipolar coupling restraints in conjunction with NOE distance, dihedral angle, and scalar coupling restraints. Comparison of the free ecTbetaR2 solution structure with the TGFbeta3-bound ecTbetaR2 crystal structure reveals backbone conformations that superimpose with RMSDs of 1.0 Angstrom over the regions of regular secondary structure and 1.4 Angstrom overall. The differences in structure fall mainly in loop regions that are either poorly defined by the available NMR data or are involved in crystal contacts. The noted similarities between the NMR structure of the free form and the crystal structure of the TGFbeta-bound form are also consistent with the close correspondence, 0.16 Angstrom RMSD for regions of secondary structure and 0.51 Angstrom RMSD overall, for the crystal structure of free ecTbetaR2 as compared to the crystal structure of TGFbeta3-bound ecTbetaR2. Despite the apparent similarities between the free and the bound forms, there appears to be small but significant differences in structure involving the interfacial contact region of the receptor. Measurements of backbone N-15 relaxation times and interpretation of these by the model-free formalism with axial diffusional anisotropy further reveal significant ms to mus time scale motions centered about two of the conserved disulfide bonds and in several residues that comprise the TGFbeta binding surface. Together, these observations indicate that binding likely occurs through a mechanism with a small component of induced fit character, whereby flexibility within the receptor facilitates the transition to the TGFbeta-bound state.