Cardiolipin occupancy profiles of YidC paralogs reveal the significance of respective TM2 helix residues in determining paralog-specific phenotypes.
Cardiolipin occupancy profiles of YidC paralogs reveal the significance of respective TM2 helix residues in determining paralog-specific phenotypes.
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DOI：
10.3389/fmolb.2023.1264454
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发表时间：
2023
影响因子：
5
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中科院分区：
文献类型：
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YidC 属于进化上保守的插入酶家族 YidC/Oxa1/Alb3，分别存在于细菌、线粒体和叶绿体中。与革兰氏阴性菌不同，包括变形链球菌在内的革兰氏阳性菌含有两个 YidC 旁系同源物。细菌 YidC1 与 YidC2 的旁系同源特异性表型机制部分归因于它们细胞质结构域的差异。然而，我们之前在 YidC1 跨膜螺旋 2 中发现了 W138R 功能获得性突变。YidC1W138R 大部分是 YidC2 的表型复制，但其机制仍不清楚。链球菌 YidC 的一级序列比较使我们鉴定出 YidC1W138 类似物 YidC2S152 并将其突变为 W/A，这导致 YidC2 丢失并获得 YidC1 样表型。预测的 YidC1W138/YidC2S152 面向脂质的侧链使我们提出膜磷脂在变形链球菌 YidC 旁系同源物的特定残基依赖性表型中的作用。心磷脂 (CL) 是酸胁迫期间变形链球菌细胞质膜中普遍存在的磷脂，由单个基因 cls 编码。基于相似的启动子活性增加和相似的消除表型，我们展示了酸胁迫下心磷脂和 YidC2 的协同机制。使用 Martini2.2 力场进行粗粒分子动力学模拟，在计算机上评估了 YidC1 和 YidC2 野生型和突变体与 CL 的相互作用。我们观察到二聚体蛋白与单体蛋白相比，CL 相互作用显着增加，并且在模仿其他野生型旁系同源物特征的 YidC1 和 YidC2 突变体构建体中观察到可变的 CL 占据。因此，旁系同源物特异性氨基酸-CL相互作用促成YidC1和YidC2相关表型，这些表型可以分别通过位置138或152处的点突变进行交换。
YidC belongs to an evolutionarily conserved family of insertases, YidC/Oxa1/Alb3, in bacteria, mitochondria, and chloroplasts, respectively. Unlike Gram-negative bacteria, Gram-positives including Streptococcus mutans harbor two paralogs of YidC. The mechanism for paralog-specific phenotypes of bacterial YidC1 versus YidC2 has been partially attributed to the differences in their cytoplasmic domains. However, we previously identified a W138R gain-of-function mutation in the YidC1 transmembrane helix 2. YidC1W138R mostly phenocopied YidC2, yet the mechanism remained unknown. Primary sequence comparison of streptococcal YidCs led us to identify and mutate the YidC1W138 analog, YidC2S152 to W/A, which resulted in a loss of YidC2- and acquisition of YidC1-like phenotype. The predicted lipid-facing side chains of YidC1W138/YidC2S152 led us to propose a role for membrane phospholipids in specific-residue dependent phenotypes of S. mutans YidC paralogs. Cardiolipin (CL), a prevalent phospholipid in the S. mutans cytoplasmic membrane during acid stress, is encoded by a single gene, cls. We show a concerted mechanism for cardiolipin and YidC2 under acid stress based on similarly increased promoter activities and similar elimination phenotypes. Using coarse grain molecular dynamics simulations with the Martini2.2 Forcefield, YidC1 and YidC2 wild-type and mutant interactions with CL were assessed in silico. We observed substantially increased CL interaction in dimeric versus monomeric proteins, and variable CL occupancy in YidC1 and YidC2 mutant constructs that mimicked characteristics of the other wild-type paralog. Hence, paralog-specific amino acid- CL interactions contribute to YidC1 and YidC2-associated phenotypes that can be exchanged by point mutation at positions 138 or 152, respectively.
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影响因子：
5.2
作者：
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通讯作者：
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Knapp, Bernhard;Ospina, Luis;Deane, Charlotte M.
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Deane, Charlotte M.
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作者：
de Jong, Djurre H.;Singh, Gurpreet;Marrink, Siewert J.
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Marrink, Siewert J.