DIP/Dpr interactions and the evolutionary design of specificity in protein families
DIP/Dpr interactions and the evolutionary design of specificity in protein families
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DOI：
10.1038/s41467-020-15981-8
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发表时间：
2020-05-01
影响因子：
16.6
通讯作者：
Honig, Barry
中科院分区：
文献类型：
--
作者：
Sergeeva, Alina P.;Katsamba, Phinikoula S.;Honig, Barry
密切相关的蛋白质家族成员之间的不同结合亲和力是许多生物学现象的基础，包括细胞-细胞识别。果蝇DIP和DPR蛋白通过高度特异的蛋白质-蛋白质相互作用在果蝇中介导神经元靶向。我们在这里表明，DIPS/DPR分为七个特异性亚组，由其DIP和DPR成员之间的结合偏好定义。然后，我们描述了一种基于序列、结构和能量的计算方法，结合实验结合亲和力测量，以揭示特异性是如何在规范的DIP/DPR界面上编码的。我们发现DIP/DPR亚群的结合特异性受干扰结合的“负约束”控制。为了实现特异性，每个亚组利用不同的负面限制条件组合，这些限制条件广泛分布并覆盖蛋白质-蛋白质界面的大部分。我们讨论了负限制的结构起源，以及对多蛋白质家族中结合特异性的进化起源的潜在的一般影响。DPR(缺陷鼻子延伸反应)和DPR相互作用蛋白(DPR相互作用蛋白)是免疫球蛋白样细胞-细胞黏附蛋白，形成高度特异的成对相互作用，在果蝇发育过程中控制突触连接。在这里，作者将计算方法与结合亲和力测量相结合，发现DIP/DPR结合特异性受干扰非同源结合的负面限制因素控制。
Differential binding affinities among closely related protein family members underlie many biological phenomena, including cell-cell recognition. Drosophila DIP and Dpr proteins mediate neuronal targeting in the fly through highly specific protein-protein interactions. We show here that DIPs/Dprs segregate into seven specificity subgroups defined by binding preferences between their DIP and Dpr members. We then describe a sequence-, structure- and energy-based computational approach, combined with experimental binding affinity measurements, to reveal how specificity is coded on the canonical DIP/Dpr interface. We show that binding specificity of DIP/Dpr subgroups is controlled by "negative constraints", which interfere with binding. To achieve specificity, each subgroup utilizes a different combination of negative constraints, which are broadly distributed and cover the majority of the protein-protein interface. We discuss the structural origins of negative constraints, and potential general implications for the evolutionary origins of binding specificity in multi-protein families. Dpr (Defective proboscis extension response) and DIP (Dpr Interacting Proteins) are immunoglobulin-like cell-cell adhesion proteins that form highly specific pairwise interactions, which control synaptic connectivity during Drosophila development. Here, the authors combine a computational approach with binding affinity measurements and find that DIP/Dpr binding specificity is controlled by negative constraints that interfere with non-cognate binding.