Plasmolipin (PLLP)是位于脂质流域中的一种膜蛋白，参与了髓鞘的形成。它还与许多病理过程有关，例如神经系统疾病、2型糖尿病和癌转移。为了更好地了解PLLP如何与流域成分（神经节苷脂和胆固醇）相互作用，我们进行了一项综合研究，结合了体外模拟和各种PLLP-神经节苷脂系统的物理化学相互作用测量。体外模拟研究包括在重建的膜环境中进行的分子动力学模拟。PLLP-神经节苷脂相互作用的测量是通过在神经节苷脂单层上进行的水—空气界面微张力测定实现的。我们已经阐明了PLLP与神经节苷脂GM1的相互作用方式，并在分子水平上对这种相互作用进行了表征。我们表明，GM1诱导了PLLP的细胞外环的结构化，并且这种相互作用通过细胞膜传播构象信号，涉及跨膜区域中的胆固醇分子。这种构象波最终传递到蛋白质的胞内结构域，与PLLP在信号转导中的作用一致。这项研究是我们团队提出的蛋白质结构的表观遗传维度的典型例证，该概念用于描述神经节苷脂对无序蛋白质基序的伴侣效应，该伴侣效应与脂质流域相结合。从生理学角度来看，这些数据揭示了神经节苷脂在髓鞘形成中的作用。从病理学角度来看，这项研究将有助于设计基于神经节苷脂-PLLP相互作用的创新治疗策略，用于治疗各种PLLP相关疾病。© 2023 The Author(s). Published by IMR Press.

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 in silico simulations and physicochemical measurements of molecular interactions in various PLLP-ganglioside systems.In silico 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.© 2023 The Author(s). Published by IMR Press.