mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations.
mPPases create a conserved anionic membrane fingerprint as identified via multi-scale simulations.
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DOI：
10.1371/journal.pcbi.1010578
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发表时间：
2022-10
影响因子：
4.3
通讯作者：
Kalli, Antreas C.
中科院分区：
文献类型：
--
作者：
Holmes, Alexandra O. M.;Goldman, Adrian;Kalli, Antreas C.
膜整合焦磷酸酶（mPPases）是膜结合酶，负责水解无机焦磷酸盐和跨膜转运阳离子。它们的功能对于临床相关的原生动物寄生虫的感染性和植物成熟是必不可少的。最近的发展表明，它们的机制比以前认为的更复杂，膜环境可能对它们的功能很重要。在这项工作中，我们使用多尺度分子动力学模拟首次证明，mPPases在蛋白质的远端和界面区域的4个位点形成特定的阴离子脂质相互作用。这些相互作用是保守的mPPases从Thermotoga maritima，绿豆辐射和梭菌leptum的模拟，其特征在于与正残基的相互作用的螺旋1，2，3和4的远端网站，或9，10，13和14的界面网站。由于这些螺旋在蛋白质稳定性和功能中的重要性，这些脂质相互作用可能在mPPase机制中发挥关键作用，并使未来的结构和功能研究成为可能。在这项工作中，我们证明了从两个物种的蛋白质上的脂质相互作用位点的保护，偏离他们的进化共同祖先很久以前，使用膜整合焦磷酸酶从嗜热细菌物种和植物物种。我们进一步表明，这些网站是保存在同源建模的蛋白质的同一个家庭。这种共同的脂质相互作用谱或“指纹”的保留以及我们预测该家族中其他蛋白质的能力可能表明它们比以前认为的更重要。通过确定脂质的相互作用，可以起到稳定蛋白质结构，这些属性可以被利用来解决蛋白质的结构，和界面网站的潜在参与亚基间通信可能是有用的进一步调查的催化循环，这个临床相关的膜蛋白家族。字数：140
Membrane-integral pyrophosphatases (mPPases) are membrane-bound enzymes responsible for hydrolysing inorganic pyrophosphate and translocating a cation across the membrane. Their function is essential for the infectivity of clinically relevant protozoan parasites and plant maturation. Recent developments have indicated that their mechanism is more complicated than previously thought and that the membrane environment may be important for their function. In this work, we use multiscale molecular dynamics simulations to demonstrate for the first time that mPPases form specific anionic lipid interactions at 4 sites at the distal and interfacial regions of the protein. These interactions are conserved in simulations of the mPPases from Thermotoga maritima, Vigna radiata and Clostridium leptum and characterised by interactions with positive residues on helices 1, 2, 3 and 4 for the distal site, or 9, 10, 13 and 14 for the interfacial site. Due to the importance of these helices in protein stability and function, these lipid interactions may play a crucial role in the mPPase mechanism and enable future structural and functional studies. In this work, we demonstrated conservation of lipid-interaction sites on proteins from two species that deviated from their evolutionary common ancestors a long time ago, using the membrane-integral pyrophosphatases from a thermophilic bacteria species and a plant species. We further showed that these sites are preserved in homology modelled proteins of the same family. This retention of a common lipid interaction profile or “fingerprint” and our ability to predict this for other proteins in this family may indicate that they are more integral to protein function than previously thought. By identifying lipid interactions that may act to stabilise the protein structure, these properties could be exploited to solve protein structures, and the interfacial site’s potential involvement in inter-subunit communication may be useful for further investigation of the catalytic cycle of this clinically relevant membrane protein family. Word Count: 140
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
56.9
作者：
Kellosalo, Juho;Kajander, Tommi;Goldman, Adrian
通讯作者：
Goldman, Adrian
影响因子：
18.2
作者：
Corradi, Valentina;Mendez-Villuendas, Eduardo;Tieleman, D. Peter
通讯作者：
Tieleman, D. Peter
影响因子：
3.4
作者：
Chong J;De Vecchis D;Hyman AJ;Povstyan OV;Ludlow MJ;Shi J;Beech DJ;Kalli AC
通讯作者：
Kalli AC
影响因子：
1.9
作者：
KATES, M;SYZ, JY;HAINES, TH
通讯作者：
HAINES, TH