Changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members.
Changes in dynamics upon oligomerization regulate substrate binding and allostery in amino acid kinase family members.
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DOI：
10.1371/journal.pcbi.1002201
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发表时间：
2011-09
影响因子：
4.3
通讯作者：
Bahar I
中科院分区：
文献类型：
--
作者：
Marcos E;Crehuet R;Bahar I
寡聚化是许多蛋白质的功能要求。单个单体的界面相互作用和整体堆积几何形状被视为低聚物的热力学稳定性和变构调节的重要决定因素。本研究的重点是在低聚状态下获得的动态功能的界面相互作用和整体接触拓扑结构的作用。为了这个目的，属于氨基酸激酶家族的二聚体和六聚体形式的酶的集体动力学通过弹性网络模型来检查，并且最软的集体运动（即，最低频率或全局运动模式）。值得注意的是，在没有多聚化的情况下，单个亚基可访问的最低频率模式在很大程度上在寡聚体中是保守的，这表明寡聚体利用了单个单体的内在动力学。在同一时间，低聚硬化的单体的界面区域，并赋予新的合作模式，利用完整的单体的刚体平移和旋转自由度。本研究揭示了精氨酸协同抑制六聚体N-乙酰-L-谷氨酸激酶的机制以及UMP激酶的变构调节。它还强调了特定的四元设计的意义，在选择性地确定所需的配体结合和变构活动的寡聚体动力学一致。蛋白质功能需要具有催化和结合事件的特定动力学特征的三维结构，并且在许多情况下，该结构由多于一个多肽链（也称为单体或亚基）组装形成寡聚体或多聚体而产生。蛋白质如血红蛋白或伴侣蛋白GroEL是分别由2个和14个亚基形成的寡聚体，而病毒衣壳是由数百个单体组成的多聚体。在这些情况下，子单元之间的接口和整体组装几何结构的架构在确定这些复杂结构在生理条件下能够执行的功能运动中是必不可少的。在这里，我们提出了属于氨基酸激酶家族的二聚体和六聚体蛋白质的大幅度运动的计算研究结果。我们的研究表明，在这些寡聚体蛋白质的单体的排列方式，寡聚体继承了其组件的内在动力学特征。堆积几何形状另外赋予进行涉及所有单体的高度协同构象变化的能力，并使多聚体具有生物活性。该研究强调了四元设计在有利于寡聚体动力学，使配体结合和变构调节功能的意义。
Oligomerization is a functional requirement for many proteins. The interfacial interactions and the overall packing geometry of the individual monomers are viewed as important determinants of the thermodynamic stability and allosteric regulation of oligomers. The present study focuses on the role of the interfacial interactions and overall contact topology in the dynamic features acquired in the oligomeric state. To this aim, the collective dynamics of enzymes belonging to the amino acid kinase family both in dimeric and hexameric forms are examined by means of an elastic network model, and the softest collective motions (i.e., lowest frequency or global modes of motions) favored by the overall architecture are analyzed. Notably, the lowest-frequency modes accessible to the individual subunits in the absence of multimerization are conserved to a large extent in the oligomer, suggesting that the oligomer takes advantage of the intrinsic dynamics of the individual monomers. At the same time, oligomerization stiffens the interfacial regions of the monomers and confers new cooperative modes that exploit the rigid-body translational and rotational degrees of freedom of the intact monomers. The present study sheds light on the mechanism of cooperative inhibition of hexameric N-acetyl-L-glutamate kinase by arginine and on the allosteric regulation of UMP kinases. It also highlights the significance of the particular quaternary design in selectively determining the oligomer dynamics congruent with required ligand-binding and allosteric activities. Protein function requires a three-dimensional structure with specific dynamic features for catalytic and binding events, and, in many cases, the structure results from the assembly of more than one polypeptide chain (also called monomer or subunit) to form an oligomer or multimer. Proteins such as hemoglobin or chaperonin GroEL are oligomers formed by 2 and 14 subunits, respectively, whereas virus capsids are multimers composed of hundreds of monomers. In these cases, the architecture of the interface between the subunits and the overall assembly geometry are essential in determining the functional motions that these sophisticated structures are able to perform under physiological conditions. Here we present results from our computational study of the large-amplitude motions of dimeric and hexameric proteins that belong to the Amino Acid Kinase family. Our study reveals that the monomers in these oligomeric proteins are arranged in such a way that the oligomer inherits the intrinsic dynamic features of its components. The packing geometry additionally confers the ability to perform highly cooperative conformational changes that involve all monomers and enable the biological activity of the multimer. The study highlights the significance of the quaternary design in favoring the oligomer dynamics that enables ligand-binding and allosteric regulation functions.
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影响因子：
2.9
作者：
Grueninger, Dirk;Schulz, Georg E.
通讯作者：
Schulz, Georg E.
影响因子：
9.9
作者：
通讯作者：
--
影响因子：
5.8
作者：
Eyal, Eran;Yang, Lee-Wei;Bahar, Ivet
通讯作者：
Bahar, Ivet
DOI：
10.1016/s1359-0278(97)00024-2
发表时间：
1997-01-01
期刊：
FOLDING & DESIGN
影响因子：
--
作者：
Bahar, I;Atilgan, AR;Erman, B
通讯作者：
Erman, B
影响因子：
3.2
作者：
Fernandez-Murga, M. Leonor;Rubio, Vicente
通讯作者：
Rubio, Vicente