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Role of Cholesterol in Transmembrane Dimerization of the ErbB2 Growth Factor Receptor
The Journal of Membrane Biology ( IF 2.4 ) Pub Date : 2021-01-28 , DOI: 10.1007/s00232-021-00168-z
Aiswarya B Pawar 1, 2 , Durba Sengupta 1, 2
Affiliation  

Abstract

The association of ErbB2 growth factor receptors is critical for cell growth and potentiates tumor proliferation in several cancer types. An important aspect in ErbB2 association is the role of lipids such as cholesterol, especially since their metabolism is often reprogrammed in cancer cells. Here, we have coupled metadynamics with coarse-grain simulations to identify cholesterol effects in the transmembrane dimerization of ErbB2 receptors. Overall, cholesterol interactions are observed with the receptor that directly tunes the association energetics. Several dimer conformations are identified both in the presence and absence of cholesterol, although the dimer regime appears to be more favorable in the presence of cholesterol. We observe an overall modulation of the underlying energy profile and the symmetric active and inactive conformational states are not distinguished in the presence of cholesterol. We show that cholesterol binds to the receptor transmembrane domain at a site (CRAC motif) that overlaps with the dimer interface (SmXXXSm motif). The competition between the transmembrane interactions and cholesterol interactions decides the final conformational landscape. Our work is an important step toward characterizing cholesterol effects in ErbB2 membrane receptor function.

Graphic Abstract



中文翻译:

胆固醇在 ErbB2 生长因子受体跨膜二聚化中的作用

摘要

ErbB2 生长因子受体的结合对细胞生长至关重要,并增强了几种癌症类型的肿瘤增殖。ErbB2 关联的一个重要方面是脂质如胆固醇的作用,特别是因为它们的代谢经常在癌细胞中重新编程。在这里,我们将元动力学与粗粒模拟相结合,以识别胆固醇在 ErbB2 受体跨膜二聚化中的作用。总体而言,观察到胆固醇与直接调节关联能量的受体的相互作用。在存在和不存在胆固醇的情况下鉴定了几种二聚体构象,尽管二聚体方案似乎在存在胆固醇的情况下更有利。我们观察到潜在能量分布的整体调制,并且在胆固醇存在时不区分对称的活性和非活性构象状态。我们显示胆固醇在与二聚体界面(SmXXXSm 基序)重叠的位点(CRAC 基序)与受体跨膜结构域结合。跨膜相互作用和胆固醇相互作用之间的竞争决定了最终的构象景观。我们的工作是朝着表征 ErbB2 膜受体功能中的胆固醇效应迈出的重要一步。跨膜相互作用和胆固醇相互作用之间的竞争决定了最终的构象景观。我们的工作是朝着表征 ErbB2 膜受体功能中的胆固醇效应迈出的重要一步。跨膜相互作用和胆固醇相互作用之间的竞争决定了最终的构象景观。我们的工作是朝着表征 ErbB2 膜受体功能中的胆固醇效应迈出的重要一步。

图形摘要

更新日期:2021-01-28
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