AbstractAdhesion G Protein-Coupled Receptors (aGPCRs) are key cell-adhesion molecules involved in numerous physiological functions. aGPCRs have large multi-domain extracellular regions (ECRs) containing a conserved GAIN domain that precedes their seven-pass transmembrane domain (7TM). Ligand binding and mechanical force applied on the ECR regulate receptor function.

摘要粘附G蛋白偶联受体（aGPCRs）是参与多种生理功能的关键细胞粘附分子。AGPCR具有较大的多结构域胞外区域（ECR），其中包含一个保守的GAIN结构域，该结构域位于其七次跨膜结构域（7TM）之前。施加在ECR上的配体结合和机械力调节受体功能。

However, how the ECR communicates with the 7TM remains elusive, because the relative orientation and dynamics of the ECR and 7TM within a holoreceptor is unclear. Here, we describe the cryo-EM reconstruction of an aGPCR, Latrophilin3/ADGRL3, and reveal that the GAIN domain adopts a parallel orientation to the transmembrane region and has constrained movement.

然而，ECR如何与7TM通信仍然难以捉摸，因为ECR和7TM在全受体内的相对方向和动力学尚不清楚。在这里，我们描述了aGPCR，Latrophilin3/ADGRL3的低温EM重建，并揭示了GAIN结构域与跨膜区域平行，并且运动受限。

Single-molecule FRET experiments unveil three slow-exchanging FRET states of the ECR relative to the transmembrane region within the holoreceptor. GAIN-targeted antibodies, and cancer-associated mutations at the GAIN-7TM interface, alter FRET states, cryo-EM conformations, and receptor signaling. Altogether, this data demonstrates conformational and functional coupling between the ECR and 7TM, suggesting an ECR-mediated mechanism for aGPCR activation..

单分子FRET实验揭示了ECR相对于全受体内跨膜区域的三种缓慢交换FRET状态。GAIN靶向抗体和GAIN-7TM界面处的癌症相关突变会改变FRET状态，冷冻EM构象和受体信号传导。总而言之，该数据证明了ECR和7TM之间的构象和功能耦合，表明了ECR介导的aGPCR激活机制。。

IntroductionWith 33 members in humans, the adhesion G protein-coupled receptors (aGPCRs) make up the second-largest GPCR family, but the molecular mechanisms underlying their activation and modulation are not fully understood1,2,3. Genetic studies have demonstrated critical roles for aGPCRs in development, immunity, and neurobiology, including brain development4,5,6,7,8, myelination9, brain angiogenesis10, and neural tube development11,12.

引言人类有33个成员，粘附G蛋白偶联受体（aGPCRs）构成第二大GPCR家族，但其激活和调节的分子机制尚未完全了解1,2,3。遗传学研究表明，aGPCRs在发育，免疫和神经生物学中起着关键作用，包括大脑发育4,5,6,7,8，髓鞘形成9，脑血管生成10和神经管发育11,12。

They are also linked to various diseases such as neurodevelopmental disorders, deafness, male infertility, attention deficit-hyperactivity disorder, schizophrenia, immune disorders, and cancers6,13,14,15,16. While 35% of FDA-approved drugs target GPCRs17, aGPCRs have yet to be targeted therapeutically, primarily due to our limited understanding of their functional modulation.The distinctive chimeric architecture of aGPCRs differentiates them from conventional GPCRs13,18.

它们还与各种疾病有关，如神经发育障碍，耳聋，男性不育，注意力缺陷多动障碍，精神分裂症，免疫障碍和癌症6,13,14,15,16。虽然35%的FDA批准的药物靶向GPCRs17，但aGPCRs尚未成为治疗靶点，主要是由于我们对其功能调节的了解有限。aGPCRs独特的嵌合结构使其与传统的GPCR区分开来13,18。

In addition to their signaling seven transmembrane (7TM) helices that are characteristic of all GPCRs, aGPCRs also have large (up to 6000 residues), multidomain extracellular regions (ECRs). The ECR is characterized by a conserved GPCR Autoproteolysis INducing (GAIN) domain that is always positioned at the far C-terminus of the ECR, in close proximity to the 7TM region19.

除了它们的信号传导七个跨膜（7TM）螺旋是所有GPCR的特征外，AGPCR还具有大的（多达6000个残基）多域细胞外区域（ECR）。ECR的特征在于保守的GPCR自蛋白水解诱导（GAIN）结构域，其总是位于ECR的远C末端，紧邻7TM区域19。

The GAIN domain contains an autoproteolysis site between its last two β-strands, and it is cleaved during protein maturation in the endoplasmic reticulum19,20,21. After autoproteolysis, the cleaved fragments stay non-covalently connected on the cell surface. The multidomain structure of the ECR allows it to interact with protein ligands found on adjacent cells or within the extracellular matrix.

GAIN结构域在其最后两条β链之间包含一个自蛋白水解位点，并且在内质网中的蛋白质成熟过程中被切割19,20,21。自蛋白水解后，切割的片段在细胞表面保持非共价连接。ECR的多结构域结构使其能够与相邻细胞或细胞外基质中发现的蛋白质配体相互作用。

These interactions give rise to mechanical forces that are key for regulating receptor activation by modul.

这些相互作用产生的机械力是调节modul受体激活的关键。

Data availability

数据可用性

The cryo-EM density map has been deposited in the Electron Microscopy Data Bank under accession code EMD-43523, and the coordinates for the model of HormR/GAIN domains of ADGRL3 in complex with sAB LK3 generated in this study have been deposited in the Protein Data Bank under accession code PDB 8vti.

低温电磁密度图已以登录号EMD-43523保存在电子显微镜数据库中，并且本研究中产生的与sAB LK3复合的ADGRL3的HormR/GAIN结构域模型的坐标已保存在蛋白质数据库中，登录号为PDB 8vti。

The available structure of the apo-state 7TM region of ADGRL3 referenced in this work is available under the accession code 8jmt. Sample single molecule image data of ADGRL3 WT and ADGRL3 S810L/E811Q has been deposited in the Harvard Dataverse repository at https://doi.org/10.7910/DVN/W446VI. All data supporting the findings of this study are available within the article and Supplementary Information/Source Data files.

这项工作中引用的ADGRL3的载脂蛋白状态7TM区域的可用结构可在登录号8jmt下获得。ADGRL3 WT和ADGRL3 S810L/E811Q的样品单分子图像数据已保存在哈佛大学Dataverse存储库中https://doi.org/10.7910/DVN/W446VI.。

Raw smFRET traces data sets can be provided upon request to the corresponding author R.V. Source data are provided with this paper..

。。

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Zhang，J。等人。T盒核糖开关的特定结构元件驱动tRNA配体的两步结合。Elife 7，e39518（2018）。下载参考文献致谢我们感谢James Fuller博士和芝加哥大学高级电子显微镜核心设施（RRID:SCR\U 019198）的工作人员以及Dr。

Tara L. Fox of the NCEF facility for assistance with cryo-EM data collection. We also thank Dr. Andrew Kruse and Dr. Cheng Zhang for helpful discussions regarding membrane protein expression and purification, Dr. James Fuller, Dr. Jingxian Li, Dr. Navid Bavi, and Dr. Minglei Zhao for valuable advice regarding cryo-EM sample preparation and data processing.

NCEF设施的Tara L.Fox协助冷冻电磁数据收集。我们还感谢Andrew Kruse博士和Cheng Zhang博士就膜蛋白表达和纯化进行了有益的讨论，感谢James Fuller博士，Jingxian Li博士，Navid Bavi博士和Minglei Zhao博士就低温电磁样品制备和数据处理提供了宝贵的建议。

We thank Dr. Michael R. Schamber and Cole J. Wilson for their help with cloning. This work was supported by grants R35 GM148412 (to D.A.), R01 GM134035-01 (to D.A.), R01 GM140272 (to R.V.) F32 GM142266 (to S.J.B.), R01 GM117372 (to A.A.K.), and C-093 from the Chicago Biomedical Consortium (to D.A. and R.V.).

我们感谢Michael R.Schamber博士和Cole J.Wilson博士在克隆方面的帮助。这项工作得到了资助R35 GM148412（授予D.A.），R01 GM134035-01（授予D.A.），R01 GM140272（授予R.V.），F32 GM142266（授予S.J.B.），R01 GM117372（授予A.A.K.）和芝加哥生物医学协会（授予D.A.和R.V.）的C-093的支持。

G.S. is supported by the Molecular Biophysics Training Program from NIGMS/NIH (T32GM140995). This research was, in part, supported by the National Cancer Institute’s National Cryo-EM Facility at the Frederick National Laboratory for Cancer Research under contract HSSN261200800001E.Author informationAuthor notesPrzemysław DutkaPresent address: Department of Structural Biology, Genentech, South San Francisco, CA, USAThese authors contributed equally: Szymon P.

G、 美国由NIGMS/NIH的分子生物物理学培训计划（T32GM140995）支持。根据合同HSSN261200800001E，这项研究部分得到了位于弗雷德里克国家癌症研究实验室的国家癌症研究所国家低温电磁设施的支持。作者信息作者注释Sprzemysław DutkaPresent地址：美国加利福尼亚州南旧金山基因泰克结构生物学系这些作者做出了同样的贡献：Szymon P。

Kordon, Kristina Cechova.Authors and AffiliationsDepartment of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USASzymon P. Kordon, Sumit J. Bandekar, Katherine Leon, Przemysław Dutka, Anthony A. Kossiakoff & Demet AraçNeuroscience Institute, The University of Chicago, Chicago, IL, USASzymon P.

科顿，克里斯蒂娜·切科娃。作者和附属机构芝加哥大学生物化学与分子生物学系，伊利诺伊州芝加哥，USASzymon P.Kordon，Sumit J.Bandekar，Katherine Leon，Przemysław Dutka，Anthony A.Kossiakoff＆Demet AraçNeuroscience Institute，芝加哥大学，伊利诺伊州芝加哥，USASzymon P。

Kordon, Sumit J.

苏米特·科登。

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PubMed Google ScholarContributionsS.P.K., K.C., R.V., and D.A. designed all experiments and interpreted results. K.C. and K.L. cloned constructs for smFRET and protein expression and purification experiments. S.P.K. expressed and purified all proteins (with assistance from K.L.), prepared EM samples, and performed specimen screening, data collection and cryo-EM data analysis.

PubMed谷歌学术贡献。P、 K.，K.C.，R.V。和D.A.设计了所有实验并解释了结果。K、 C.和K.L.克隆的构建体，用于smFRET和蛋白质表达和纯化实验。S、 P.K.表达并纯化了所有蛋白质（在K.L.的帮助下），制备了EM样品，并进行了样品筛选，数据收集和冷冻EM数据分析。

S.J.B. assisted with cryo-EM map calculation and built and refined the HormR/GAIN structure. K.C. prepared smFRET specimens and performed smFRET measurements (with assistance from G.S.) and data analysis. P.D. carried out phage display selection and sABs characterization. S.P.K. performed cell-based signaling assays.

S、 J.B.协助低温电磁图计算，并建立和完善了HormR/GAIN结构。K、 C.制备smFRET样品并进行smFRET测量（在G.S.的帮助下）和数据分析。P、 D.进行噬菌体展示选择和sABs表征。S、 P.K.进行了基于细胞的信号传导测定。

D.A., S.P.K., R.V., and K.C. wrote the manuscript with assistance from, S.J.B. and P.D. D.A., R.V., and A.A.K. supervised the project.Corresponding authorsCorrespondence to.

D、 A.，S.P.K.，R.V.和K.C.在S.J.B.和P.D.D.A.，R.V.和A.A.K.的协助下撰写了手稿，并监督了该项目。通讯作者通讯。

Reza Vafabakhsh or Demet Araç.Ethics declarations

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Competing interests

相互竞争的利益

The authors declare no competing interests.

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Nature Communications thanks Antony Boucard and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleKordon, S.P., Cechova, K., Bandekar, S.J. et al. Conformational coupling between extracellular and transmembrane domains modulates holo-adhesion GPCR function.

转载和许可本文引用本文Kordon，S.P.，Cechova，K.，Bandekar，S.J。等人。细胞外和跨膜结构域之间的构象偶联调节全粘附GPCR功能。

Nat Commun 15, 10545 (2024). https://doi.org/10.1038/s41467-024-54836-4Download citationReceived: 28 January 2024Accepted: 20 November 2024Published: 04 December 2024DOI: https://doi.org/10.1038/s41467-024-54836-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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