Altered lipid metabolism has been linked to cancer development and progression. Several roles have been attributed to the increased saturation and length of lipid acyl tails observed in tumors, but its effect on signaling receptors is still emerging. In this work, we have analyzed the lipid dependence of the ErbB2 growth factor receptor dimerization that plays an important role in the pathogenesis of breast cancer. We have performed coarse-grain ensemble molecular dynamics simulations to comprehensively sample the ErbB2 monomer-dimer association. Our results indicate a dynamic dimer state with a complex conformational landscape that is modulated with increasing lipid tail length. We resolve the native N-terminal "active" and C-terminal "inactive" conformations in all membrane compositions. However, the relative population of the N-terminal and C-terminal conformers is dependent on length of the saturated lipid tails. In short-tail membranes, additional non-specific dimers are observed which are reduced or absent in long-tailed bilayers. Our results indicate that the relative population as well as the structure of the dimer state is modulated by membrane composition. We have correlated these differences to local perturbations of the membrane around the receptor. Our work is an important step in characterizing ErbB dimers in healthy and diseased states and emphasize the importance of sampling lipid dynamics in understanding receptor association.

中文翻译：

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ErbB2生长因子受体二聚体的脂质依赖性构象景观。

脂质代谢改变与癌症的发生和发展有关。在肿瘤中观察到脂质酰基尾巴的饱和度和长度增加，这归因于几种作用，但其对信号受体的作用仍在显现。在这项工作中，我们分析了ErbB2生长因子受体二聚体的脂质依赖性，该依赖性在乳腺癌的发病机理中起重要作用。我们已经执行了粗粒集成分子动力学模拟，以全面采样ErbB2单体-二聚体缔合。我们的结果表明动态二聚体状态具有复杂的构象态势，并随着脂质尾巴长度的增加而受到调节。我们解析了所有膜成分中的天然N端“活性”和C端“非活性”构象。然而，N末端和C末端构象异构体的相对种群取决于饱和脂质尾巴的长度。在短尾膜中，观察到另外的非特异性二聚体，其在长尾双层中减少或不存在。我们的结果表明，相对种群以及二聚体状态的结构受膜组成的调节。我们已经将这些差异与受体周围膜的局部扰动相关联。我们的工作是表征健康和患病状态下ErbB二聚体的重要步骤，并强调了采样脂质动力学对理解受体缔合的重要性。观察到另外的非特异性二聚体，其在长尾双层中减少或不存在。我们的结果表明，相对种群以及二聚体状态的结构受膜组成的调节。我们已经将这些差异与受体周围膜的局部扰动相关联。我们的工作是表征健康和患病状态下ErbB二聚体的重要步骤，并强调了采样脂质动力学对理解受体缔合的重要性。观察到另外的非特异性二聚体，其在长尾双层中减少或不存在。我们的结果表明，相对种群以及二聚体状态的结构受膜组成的调节。我们已经将这些差异与受体周围膜的局部扰动相关联。我们的工作是表征健康和患病状态下ErbB二聚体的重要步骤，并强调了采样脂质动力学对理解受体缔合的重要性。