Climbing Up and Down Binding Landscapes through Deep Mutational Scanning of Three Homologous Protein-Protein Complexes.
Climbing Up and Down Binding Landscapes through Deep Mutational Scanning of Three Homologous Protein-Protein Complexes.
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DOI：
10.1021/jacs.1c08707
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发表时间：
2021-10-20
影响因子：
15
通讯作者：
Shifman JM
中科院分区：
文献类型：
--
作者：
Heyne M;Shirian J;Cohen I;Peleg Y;Radisky ES;Papo N;Shifman JM
蛋白质-蛋白质相互作用（PPI）已经发展到显示出可以支持其功能的结合亲和力。因此，同源和非同源PPI在结构上可能高度相似，但结合亲和力存在巨大差异。为了理解这一现象，我们研究了三个同源蛋白酶抑制剂PPI，跨越9个数量级的结合亲和力。使用结合蛋白质随机化、亲和力分选、深度测序和数据标准化的最先进方法，我们报告了从数万个单突变和双突变中收集的三种PPI的ΔΔGbind值组成的定量结合景观。我们发现，结合景观的三个配合物是惊人的不同，并依赖于PPI的进化最优性。我们观察到三种PPI突变之间的不同模式的耦合，其中负上位性和正上位性分别最常出现在热点和冷点位置。这里观察到的进化趋势可能对细胞中的其他生物复合体具有普遍性。
Protein–protein interactions (PPIs) have evolved to display binding affinities that can support their function. As such, cognate and noncognate PPIs could be highly similar structurally but exhibit huge differences in binding affinities. To understand this phenomenon, we study three homologous protease–inhibitor PPIs that span 9 orders of magnitude in binding affinity. Using state-of-the-art methodology that combines protein randomization, affinity sorting, deep sequencing, and data normalization, we report quantitative binding landscapes consisting of ΔΔGbind values for the three PPIs, gleaned from tens of thousands of single and double mutations. We show that binding landscapes of the three complexes are strikingly different and depend on the PPI evolutionary optimality. We observe different patterns of couplings between mutations for the three PPIs with negative and positive epistasis appearing most frequently at hot-spot and cold-spot positions, respectively. The evolutionary trends observed here are likely to be universal to other biological complexes in the cell.
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