与全长螯合素脂肪因子结合的 G 蛋白偶联受体 GPR1 的结构揭示了一种类似于趋化因子的反向结合模式。

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences PLoS Biology Pub Date : 2024-10-28 eCollection Date: 2024-10-01 DOI:10.1371/journal.pbio.3002838
Aijun Liu, Yezhou Liu, Geng Chen, Wenping Lyu, Fang Ye, Junlin Wang, Qiwen Liao, Lizhe Zhu, Yang Du, Richard D Ye
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引用次数: 0

摘要

螯合素是一种脂肪因子,对部分白细胞具有趋化活性。螯合素与 3 种 G 蛋白偶联受体结合,包括趋化因子样受体 1(CMKLR1)、G 蛋白偶联受体 1(GPR1)和 C-C 趋化因子样受体 2(CCRL2)。在这里,我们报告了 GPR1 在全长螯合素或其 C 端非肽(C9,YFPGQFAFS)的刺激下能够发出 Gi 信号。我们展示了分别与全长螯合素和 C9 肽结合的 Gi 偶联 GPR1 的高分辨率冷冻电镜结构。C9 插入跨膜(TM)结合口袋对于 GPR1 信号传导是必要且充分的,而全长螯合素则利用其笨重的 N 端核心与位于 GPR1 N 端的 β 链相互作用。这种相互作用涉及到全长螯合素的多条 β 链,形成了一个 β 片层,作为 TM 结合袋的 "盖子",根据分子动力学模拟和自由能谱分析,去除它的能量代价很高。结合功能测试的结果,我们的结构模型解释了为什么 C9 是 GPR1 的激活肽,以及全长螯合素如何使用 "双位点 "模型来增强与 GPR1 的相互作用。
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Structure of G protein-coupled receptor GPR1 bound to full-length chemerin adipokine reveals a chemokine-like reverse binding mode.

Chemerin is an adipokine with chemotactic activity to a subset of leukocytes. Chemerin binds to 3 G protein-coupled receptors, including chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C chemokine receptor-like 2 (CCRL2). Here, we report that GPR1 is capable of Gi signaling when stimulated with full-length chemerin or its C-terminal nonapeptide (C9, YFPGQFAFS). We present high-resolution cryo-EM structures of Gi-coupled GPR1 bound to full-length chemerin and to the C9 peptide, respectively. C9 insertion into the transmembrane (TM) binding pocket is both necessary and sufficient for GPR1 signaling, whereas the full-length chemerin uses its bulky N-terminal core for interaction with a β-strand located at the N-terminus of GPR1. This interaction involves multiple β-strands of full-length chemerin, forming a β-sheet that serves as a "lid" for the TM binding pocket and is energetically expensive to remove as indicated by molecular dynamics simulations with free energy landscape analysis. Combining results from functional assays, our structural model explains why C9 is an activating peptide at GPR1 and how the full-length chemerin uses a "two-site" model for enhanced interaction with GPR1.

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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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