Lorent Joseph H, Cabrera-Jojoa Angela, Levental Kandice R, Levental Ilya, Lyman Edward
Cellular and Molecular Pharmacology (FACM), Louvain Drug Research Institute, UCLouvain, Avenue Mounier 73/1, B-1200 Brussels, Belgium.
Department of Physics and Astronomy, University of Delaware, Newark, DE, USA.
Faraday Discuss. 2025 Aug 13;259(0):597-613. doi: 10.1039/d4fd00199k.
Plasma membranes are asymmetric, with each monolayer presenting specific lipid compositions and biophysical properties. Transmembrane domains (TMDs) of single-pass transmembrane proteins (spTMPs) have adapted their physico-chemical properties to these asymmetric constraints. In this study, we analysed the structural features of such TMDs across the tree of life to obtain information about their interaction with asymmetric membrane bilayers and predict species-specific membrane properties. We observed that TMDs in the plasma membranes of all eukaryotic species possess asymmetries in lipid accessible surface area (ASA), hydrophobicity, aromaticity and charge. Bacteria deviate from this trend, with strong differences between bacterial clades. Notably, TMDs in the Golgi and the endoplasmic reticulum of eukaryotic species display inverted profiles for accessible surface area, hydrophobicity and aromaticity compared to their plasma-membrane counterparts. To determine how well TMD profiles reflect average membrane properties, we performed molecular dynamics simulations of a spTMP in an asymmetric lipid bilayer whose composition approximates the human plasma membrane. The simulated spTMP was chosen to represent the average TMD properties of the human proteome. We compared the electron density profiles of the simulated asymmetric membrane to the average TMD profiles derived from the human proteome and observed that phospholipid acyl-chain density overlapped very well with TMD hydrophobicity, and phosphate group density with TMD charge. The profiles of phospholipid unsaturation in the acyl chains overlapped well with the average location of TMD phenylalanines in the cytoplasmic leaflet, while there was additional accumulation of large hydrophobic and aromatic residues in the membrane midplane, which had low acyl-chain density. This study reveals the complementarity of membrane and TMD properties in asymmetric membranes, suggesting that the properties of TMDs can be used to make predictions about the properties of their solvating membranes.
质膜是不对称的，每个单分子层都具有特定的脂质组成和生物物理特性。单次跨膜蛋白（spTMP）的跨膜结构域（TMD）已使其物理化学性质适应这些不对称限制。在本研究中，我们分析了生命之树中此类TMD的结构特征，以获取有关它们与不对称膜双层相互作用的信息，并预测物种特异性的膜特性。我们观察到，所有真核生物物种质膜中的TMD在脂质可及表面积（ASA）、疏水性、芳香性和电荷方面都存在不对称性。细菌偏离了这一趋势，不同细菌类群之间存在很大差异。值得注意的是，与真核生物物种质膜中的TMD相比，其高尔基体和内质网中的TMD在可及表面积、疏水性和芳香性方面呈现出相反的分布。为了确定TMD分布能多好地反映平均膜特性，我们在一个组成近似人类质膜的不对称脂质双层中对一个spTMP进行了分子动力学模拟。选择模拟的spTMP来代表人类蛋白质组的平均TMD特性。我们将模拟的不对称膜的电子密度分布与源自人类蛋白质组的平均TMD分布进行了比较，观察到磷脂酰基链密度与TMD疏水性非常好地重叠，而磷酸基团密度与TMD电荷重叠。酰基链中磷脂不饱和度的分布与TMD苯丙氨酸在细胞质小叶中的平均位置很好地重叠，而在膜中间平面存在大量疏水和芳香残基的额外积累，该区域的酰基链密度较低。这项研究揭示了不对称膜中膜和TMD特性的互补性，表明TMD的特性可用于预测其溶剂化膜的特性。
