Bilayer lipids modulate ligand binding to atypical chemokine receptor 3.

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Structure Pub Date : 2024-08-08 Epub Date: 2024-05-21 DOI:10.1016/j.str.2024.04.018

Stefanie Alexandra Eberle, Martin Gustavsson

引用次数: 0

Abstract

Chemokine receptors belong to the large class of G protein-coupled receptors (GPCRs) and are involved in a number of (patho)physiological processes. Previous studies highlighted the importance of membrane lipids for modulating GPCR structure and function. However, the underlying mechanisms of how lipids regulate GPCRs are often poorly understood. Here, we report that anionic lipid bilayers increase the binding affinity of the chemokine CXCL12 for the atypical chemokine receptor 3 (ACKR3) by modulating the CXCL12 binding kinetics. Notably, the anionic bilayer favors CXCL12 over the more positively charged chemokine CXCL11, which we explained by bilayer interactions orienting CXCL12 but not CXCL11 for productive ACKR3 binding. Furthermore, our data suggest a stabilization of active ACKR3 conformations in anionic bilayers. Taken together, the described regulation of chemokine selectivity of ACKR3 by the lipid bilayer proposes an extended version of the classical model of chemokine binding including the lipid environment of the receptor.

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双层脂质调节配体与非典型趋化因子受体 3 的结合。

趋化因子受体属于一大类 G 蛋白偶联受体（GPCR），参与了许多（病理）生理过程。以往的研究强调了膜脂在调节 GPCR 结构和功能方面的重要性。然而，人们对脂质如何调节 GPCR 的内在机制往往知之甚少。在这里，我们报告了阴离子脂质双层膜通过调节 CXCL12 的结合动力学，增加了趋化因子 CXCL12 与非典型趋化因子受体 3（ACKR3）的结合亲和力。值得注意的是，阴离子双分子层偏向于 CXCL12，而不是带正电荷的趋化因子 CXCL11，我们对此的解释是，双分子层相互作用使 CXCL12 而不是 CXCL11 定向，以促进 ACKR3 的结合。此外，我们的数据还表明 ACKR3 在阴离子双分子层中的活性构象趋于稳定。综上所述，所描述的脂质双分子层对 ACKR3 的趋化因子选择性的调节，提出了包括受体脂质环境在内的趋化因子结合经典模型的扩展版本。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.