Ancestral Protein Reconstruction Yields Insights into Adaptive Evolution of Binding Specificity in Solute-Binding Proteins
Ancestral Protein Reconstruction Yields Insights into Adaptive Evolution of Binding Specificity in Solute-Binding Proteins
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DOI：
10.1016/j.chembiol.2015.12.010
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发表时间：
2016-02-18
影响因子：
8.6
通讯作者：
Jackson, Colin J.
中科院分区：
文献类型：
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作者：
Clifton, Ben E.;Jackson, Colin J.
蛋白质的混杂功能是蛋白质进化中功能新颖性的重要储备，但结合混杂性的分子基础仍然难以捉摸。我们使用祖先蛋白质重建来通过实验表征极性氨基酸结合蛋白家族功能扩展中的进化中间体，该家族已经进化为以高亲和力和特异性结合多种氨基酸。与 L-精氨酸和 L-谷氨酰胺复合的祖先精氨酸结合蛋白的高分辨率晶体结构表明，L-谷氨酰胺的混杂结合是通过多尺度构象可塑性、水介导的相互作用以及对 L-谷氨酰胺结合产生的替代构象亚状态的选择来实现的。从这种祖先蛋白质进化出专门的谷氨酰胺结合蛋白是通过从蛋白质-配体界面置换水分子来实现的，从而减少了与混杂相互作用相关的熵损失。这些结果为结合特异性进化中混杂相互作用的共同选择提供了结构和热力学基础。
The promiscuous functions of proteins are an important reservoir of functional novelty in protein evolution, but the molecular basis for binding promiscuity remains elusive. We used ancestral protein reconstruction to experimentally characterize evolutionary intermediates in the functional expansion of the polar amino acid-binding protein family, which has evolved to bind a variety of amino acids with high affinity and specificity. High-resolution crystal structures of an ancestral arginine-binding protein in complex with L-arginine and L-glutamine show that the promiscuous binding of L-glutamine is enabled by multi-scale conformational plasticity, water-mediated interactions, and selection of an alternative conformational substate productive for L-glutamine binding. Evolution of specialized glutamine-binding proteins from this ancestral protein was achieved by displacement of water molecules from the protein-ligand interface, reducing the entropic penalty associated with the promiscuous interaction. These results provide a structural and thermodynamic basis for the co-option of a promiscuous interaction in the evolution of binding specificity.