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Dynamics-function relationship in the catalytic domains of N-terminal acetyltransferases.
Computational and Structural Biotechnology Journal ( IF 6 ) Pub Date : 2020-03-03 , DOI: 10.1016/j.csbj.2020.02.017
Angèle Abboud 1, 2 , Pierre Bédoucha 1, 2 , Jan Byška 1, 3 , Thomas Arnesen 4, 5, 6 , Nathalie Reuter 2, 7
Affiliation  

N-terminal acetyltransferases (NATs) belong to the superfamily of acetyltransferases. They are enzymes catalysing the transfer of an acetyl group from acetyl coenzyme A to the N-terminus of polypeptide chains. N-terminal acetylation is one of the most common protein modifications. To date, not much is known on the molecular basis for the exclusive substrate specificity of NATs. All NATs share a common fold called GNAT. A characteristic of NATs is the β6β7 hairpin loop covering the active site and forming with the α1α2 loop a narrow tunnel surrounding the catalytic site in which cofactor and polypeptide meet and exchange an acetyl group.

We investigated the dynamics-function relationships of all available structures of NATs covering the three domains of Life. Using an elastic network model and normal mode analysis, we found a common dynamics pattern conserved through the GNAT fold; a rigid V-shaped groove formed by the β4 and β5 strands and splitting the fold in two dynamical subdomains. Loops α1α2, β3β4 and β6β7 all show clear displacements in the low frequency normal modes. We characterized the mobility of the loops and show that even limited conformational changes of the loops along the low-frequency modes are able to significantly change the size and shape of the ligand binding sites. Based on the fact that these movements are present in most low-frequency modes, and common to all NATs, we suggest that the α1α2 and β6β7 loops may regulate ligand uptake and the release of the acetylated polypeptide.



中文翻译:

N末端乙酰基转移酶催化域中的动力学功能关系。

N-末端乙酰转移酶(NAT)属于乙酰转移酶的超家族。它们是催化乙酰基从乙酰辅酶A转移到多肽链N端的酶。N末端乙酰化是最常见的蛋白质修饰之一。迄今为止,就分子方面而言,对于NAT的唯一底物特异性知之甚少。所有NAT都共享一个称为GNAT的折叠。NATs的一个特征是β6β7发夹环覆盖活性位点,并与α1α2环一起形成围绕催化位点的狭窄通道,辅因子和多肽在其中结合并交换乙酰基。

我们调查了涵盖生命三个域的所有可用NAT结构的动力学-功能关系。使用弹性网络模型和正常模式分析,我们发现了通过GNAT折叠守恒的常见动力学模式。由β4和β5链形成的刚性V形凹槽,将褶皱分成两个动态子域。循环α1α2,β3β4和β6β7在低频正常模式下均显示清晰的位移。我们表征了环的移动性,并显示出即使沿低频模式有限的环构象变化也能够显着改变配体结合位点的大小和形状。基于这些运动存在于大多数低频模式中且为所有NAT共同的事实,

更新日期:2020-03-03
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