Lipid discovery enabled by sequence statistics and machine learning.
Lipid discovery enabled by sequence statistics and machine learning.
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通过序列统计和机器学习实现脂质发现。
DOI：
10.1101/2023.10.12.562061
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Palmer,KelliL
中科院分区：
文献类型：
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作者：
Christensen,PriyaM;Martin,Jonathan;Uppuluri,Aparna;Joyce,LukeR;Wei,Yahan;Guan,Ziqiang;Morcos,Faruck;Palmer,KelliL
细菌的膜是复杂和动态的，是由一系列进化压力引起的。通过共价脂质修饰改变膜组成的一种酶是MprF。我们最近发现，无乳链球菌MprF合成赖氨酰-磷脂酰甘油（Lys-PG）从阴离子PG，和一种新的阳离子脂质，赖氨酰-葡萄糖基-二酰基甘油（Lys-Glc-DAG），从中性糖脂Glc-DAG。这个意想不到的结果促使我们研究Lys-Glc-DAG是否发生在其他含有MprF的细菌中，以及是否存在其他新的MprF产物。在这里，我们研究了决定MprF底物特异性的蛋白质序列特征。首先，成对分析鉴定了几种合成Lys-Glc-DAG的链球菌MprF。其次，一种受限的玻尔兹曼机器引导方法使我们发现了肠球菌中MprF的一种全新底物，二葡糖基-二酰基甘油（Glc 2-DAG），以及一组使用MprF修饰糖脂底物的扩展生物。总的来说，我们将大量可用的序列数据与机器学习相结合，对整个细菌结构域的MprF序列的进化约束进行建模，从而鉴定出一种新型阳离子脂质。
Bacterial membranes are complex and dynamic, arising from an array of evolutionary pressures. One enzyme that alters membrane compositions through covalent lipid modification is MprF. We recently identified that Streptococcus agalactiae MprF synthesizes lysyl-phosphatidylglycerol (Lys-PG) from anionic PG, and a novel cationic lipid, lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG), from neutral glycolipid Glc-DAG. This unexpected result prompted us to investigate whether Lys-Glc-DAG occurs in other MprF-containing bacteria, and whether other novel MprF products exist. Here, we studied protein sequence features determining MprF substrate specificity. First, pairwise analyses identified several streptococcal MprFs synthesizing Lys-Glc-DAG. Second, a restricted Boltzmann machine-guided approach led us to discover an entirely new substrate for MprF in Enterococcus, diglucosyl-diacylglycerol (Glc 2-DAG), and an expanded set of organisms that modify glycolipid substrates using MprF. Overall, we combined the wealth of available sequence data with machine learning to model evolutionary constraints on MprF sequences across the bacterial domain, thereby identifying a novel cationic lipid.