无声H-bond可以突变激活的高亲和性BMP-2和苯丙酸诺龙IIB型受体的相互作用。
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韦伯D, Kotzsch、镍J,念佛,医师,穆勒U,张琦,穆勒道明
无声H-bond可以突变激活的高亲和性BMP-2和苯丙酸诺龙IIB型受体的相互作用。
BMC结构生物学观点》2007年2月12日,6。doi: 10.1186 / 1472-6807-7-6。
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17295905 (在PubMed]
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背景:骨形成蛋白(bmp)是关键的监管机构在所有动物胚胎发育和产后组织内稳态。损失函数或失调的最佳管理导致严重甚至致命的疾病。转化生长因子β(及),苯丙酸诺龙、生长和分化的因素(gdf)和其他的成员及总科,bmp信号通过装配两种丝氨酸/ threonine-kinase受体链形成hetero-oligomeric中的复杂。骨形态发生蛋白配体受体相互作用非常滥交,即每个绑定多个受体各亚型,各种配体和受体结合。苯丙酸诺龙II型受体是特别感兴趣,因为他们结合大量不同的配体。除了他们作为激活素的高亲和性受体,但也为我国低亲和力受体。ActR-II ActR-IIB因此代表了一个有趣的例子如何生成的亲和力和特异性在杂乱的背景。结果:在这里,我们目前的高分辨率结构的三元复合物野生型和变体BMP-2绑定到的高亲和性I型受体BMPR-IA和低亲和力II型受体ActR-IIB并比较它们与已知结构中的二元和三元复合物BMP-2。与苯丙酸诺龙或TGF-beta3 BMP-2配体的二聚体结构的变化发生在复杂的形成。ActR-IIB绑定抗原决定基功能分析表明,疏水相互作用主导我国的低亲和力绑定; polar interactions contribute only little to binding affinity. However, a conserved H-bond in the center of the type II ligand-receptor interface, which does not contribute to binding in the BMP-2 - ActR-IIB interaction can be mutationally activated resulting in a BMP-2 variant with high-affinity for ActR-IIB. Further mutagenesis studies were performed to elucidate the binding mechanism allowing us to construct BMP-2 variants with defined type II receptor binding properties. CONCLUSION: Binding specificity of BMP-2 for its three type II receptors BMPR-II, Act-RII and ActR-IIB is encoded on single amino acid level. Exchange of only one or two residues results in BMP-2 variants with a dramatically altered type II receptor specificity profile, possibly allowing construction of BMP-2 variants that address a single type II receptor. The structure-/function studies presented here revealed a new mechanism, in which the energy contribution of a conserved H-bond is modulated by surrounding intramolecular interactions to achieve a switch between low- and high-affinity binding.