Department of Biology, Faculty of Medicine, Aix-Marseille University, INSERM UMR_S 1072, Marseille, France.
School of Medicine, University Hospital of Wales Heath Park, 14 4XN Cardiff CF, UK.
Front Biosci (Landmark Ed). 2023 Aug 7;28(8):157. doi: 10.31083/j.fbl2808157.
Plasmolipin (PLLP) is a membrane protein located in lipid rafts that participates in the formation of myelin. It is also implicated in many pathologies, such as neurological disorders, type 2 diabetes, and cancer metastasis. To better understand how PLLP interacts with raft components (gangliosides and cholesterol), we undertook a global study combining simulations and physicochemical measurements of molecular interactions in various PLLP-ganglioside systems.
studies consisted of molecular dynamics simulations in reconstructed membrane environments. PLLP-ganglioside interaction measurements were performed by microtensiometry at the water-air interface on ganglioside monolayers.
We have elucidated the mode of interaction of PLLP with ganglioside GM1 and characterized this interaction at the molecular level. We showed that GM1 induces the structuring of the extracellular loops of PLLP and that this interaction propagates a conformational signal through the plasma membrane, involving a cholesterol molecule located between transmembrane domains. This conformational wave is finally transmitted to the intracellular domain of the protein, consistent with the role of PLLP in signal transduction.
This study is a typical example of the epigenetic dimension of protein structure, a concept developed by our team to describe the chaperone effect of gangliosides on disordered protein motifs which associate with lipid rafts. From a physiological point of view, these data shed light on the role of gangliosides in myelin formation. From a pathological point of view, this study will help to design innovative therapeutic strategies focused on ganglioside-PLLP interactions in various PLLP-associated diseases.
质膜联蛋白（PLLP）是一种位于脂筏中的膜蛋白，参与髓鞘的形成。它还与许多病理有关，如神经紊乱、2 型糖尿病和癌症转移。为了更好地理解 PLLP 如何与筏成分（神经节苷脂和胆固醇）相互作用，我们进行了一项结合模拟和各种 PLLP-神经节苷脂系统中分子相互作用的物理化学测量的全面研究。
研究包括在重建的膜环境中的分子动力学模拟。通过在神经节苷脂单层的水-气界面上进行微张力测量，进行 PLLP-神经节苷脂相互作用测量。
我们阐明了 PLLP 与神经节苷脂 GM1 的相互作用模式，并在分子水平上表征了这种相互作用。我们表明 GM1 诱导 PLLP 的细胞外环的结构化，并且这种相互作用通过质膜传播构象信号，涉及位于跨膜结构域之间的胆固醇分子。这个构象波最终传递到蛋白质的细胞内结构域，与 PLLP 在信号转导中的作用一致。
这项研究是蛋白质结构的表观遗传维度的一个典型例子，这是我们团队开发的一个概念，用于描述神经节苷脂对与脂筏相关的无序蛋白质基序的伴侣效应。从生理学的角度来看，这些数据揭示了神经节苷脂在髓鞘形成中的作用。从病理角度来看，这项研究将有助于设计针对各种与 PLLP 相关疾病中神经节苷脂-PLLP 相互作用的创新治疗策略。
