The entropic force generated by intrinsically disordered segments tunes protein function
The entropic force generated by intrinsically disordered segments tunes protein function
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DOI：
10.1038/s41586-018-0699-5
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发表时间：
2018-11-22
期刊：
影响因子：
64.8
通讯作者：
Wood, Zachary A.
中科院分区：
文献类型：
--
作者：
Keul, Nicholas D.;Oruganty, Krishnadev;Wood, Zachary A.
蛋白质结构是动态的，可以探索一个大的构象景观（1，2。）这些结构子状态中只有一部分对蛋白质功能（如配体结合，催化和调节）很重要（3-5）进化如何塑造结构系综以优化特定功能还知之甚少（3，4）。蛋白质进化的限制之一是折叠“天然”状态的稳定性。尽管如此，44%的人类蛋白质组含有长度大于30个残基的固有无序肽段（6），其中大多数没有已知的功能（7-9）。在这里，我们表明，由一个固有的无序羧基末端（ID-尾巴）产生的熵力的人UDP-α-D-葡萄糖-6-脱氢酶（UGDH）的构象合奏转向一个具有高亲和力的变构抑制剂的substate。ID尾的功能不依赖于其序列或化学组成。相反，亲和力增强可以基于固有无序片段的长度准确预测，并且与附着于蛋白质表面的非结构化肽产生的熵力一致（10-13）。我们的数据表明，ID尾的未折叠状态纠正了UGDH的动力学和结构，以有利于抑制剂结合。因为这种熵整流器没有任何序列或结构约束，所以它是一种容易获得的适应。这个模型意味着进化选择无序片段来调整蛋白质的能量景观，这可以解释蛋白质组中内在无序的持续存在。
Protein structures are dynamic and can explore a large conformational landscape(1,2.) Only some of these structural substates are important for protein function (such as ligand binding, catalysis and regulation)(3-5) How evolution shapes the structural ensemble to optimize a spcific function is poorly understood(3,4). One of the constraints on the evolution of proteins is the stability of the folded 'native' state. Despite this, 44% of the human proteome contains intrinsically disordered peptide segments greater than 30 residues in length(6), the majority of which have no known function(7-9). Here we show that the entropic force produced by an intrinsically disordered carboxy terminus (ID-tail) shifts the conformational ensemble of human UDP-a-d-glucose-6-dehydrogenase (UGDH) towards a substate with a high affinity for an allosteric inhibitor. The function of the ID-tail does not depend on its sequence or chemical composition. Instead, the affinity enhancement can be accurately predicted based on the length of the intrinsically disordered segment, and is consistent with the entropic force generated by an unstructured peptide attached to the protein surface(10-13). Our data show that the unfolded state of the ID-tail rectifies the dynamics and structure of UGDH to favour inhibitor binding. Because this entropic rectifier does not have any sequence or structural constraints, it is an easily acquired adaptation. This model implies that evolution selects for disordered segments to tune the energy landscape of proteins, which may explain the persistence of intrinsic disorder in the proteome.