Structural Characterization of 4-1BB-Galectin-9 Complexes
4-1BB-Galectin-9 复合物的结构表征
基本信息
- 批准号:8679808
- 负责人:
- 金额:$ 8.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AgonistAnimal LectinsAnti-Inflammatory AgentsAnti-inflammatoryAntibodiesApoptosisArchitectureAutoimmune DiseasesAutoimmune ProcessBindingBiological AssayC-terminalCarbohydratesCaspaseCell CommunicationCell DeathCell membraneCell surfaceCellsClinicalClinical TrialsCommunicationComplexCrystallizationCysteine-Rich DomainDataDevelopmentDiseaseDisease modelDrug ControlsElectron MicroscopyEndothelial CellsEpithelial CellsEvaluationFamilyFamily memberFlowersGalactose Binding LectinGovernmentHomeostasisHumanHypersensitivityImmuneImmune systemImmunologyIndividualInflammationInflammatoryInstitutesInterventionLearningLengthLigand BindingLigandsLigationLinkMammalsMapsMeasuresMembraneN-terminalNegative StainingOrganOutcomePathway interactionsPersonsProtein FamilyProtein-Serine-Threonine KinasesProteinsReagentRegulationResolutionShapesSideSignal TransductionSignal Transduction PathwaySite-Directed MutagenesisStimulusStromal CellsStructureSystemT-Cell ActivationTNFRSF1A geneTNFRSF1B geneTNFRSF5 geneTumor Necrosis Factor ReceptorTumor Necrosis Factor-BetaTumor Necrosis Factor-alphaVariantX-Ray Crystallographybasebonecancer immunotherapycell typecytokinedisulfide bondextracellularin vivoinhibitor/antagonistinsightmembermonomernovelparticlepre-clinicalpublic health relevancereceptorreconstructionthree dimensional structure
项目摘要
DESCRIPTION (provided by applicant): Proteins in the tumor necrosis factor receptor superfamilies' (TNFSF/TNFRSF) are expressed on cells of the immune system, as well as on non-lymphoid structural cells such as stromal, epithelial, and endothelial cells. They have a broad range of activities in regulating cell-cell communication in many organs. TNF family molecules have canonical TNF homology domains with ¿-sandwich jelly-roll structures, and TNFR family molecules contain variable numbers of ligand-binding extracellular cysteine-rich domains (CRDs). TNFSF are active largely as cell-surface or soluble homotrimers, and the crystallized complexes of 11 interactions solved to date show that the trimers engage 3 individual TNFRSF monomers. Whether a single trimeric complex is sufficient for cellular activation is not known, but oligomers of the basic trimer may also need to form for maximal signaling. How each TNFRSF forms a functional signaling unit likely differs due to variations in the ligand structures as well as how they are recognized by the receptors. TNFSF trimers have been subdivided into 3 groups: conventional/bell-shaped, EF-disulfide bond linked/globular, and divergent/blooming flower-like. These structures have been suggested to regulate the spacing between TNFRSF monomers when binding their ligands on the cell membrane which has been theorized to control the intracellular recruitment of adaptors that link to signal transduction pathways. We have studied 4-1BBL (CD137L/TNFSF9), which was recently crystallized and shown to exert the most open structure of any of the divergent/blooming flower-like TNFSF molecules. This suggests it may not be able to cluster 3 monomeric 4-1BB (CD137/TNFRSF9) molecules as effectively as other TNFSF proteins, or may not efficiently allow oligomers to form. Therefore 4-1BBL might need additional co-receptor proteins to engage 4-1BB to aggregate into a fully functional signaling unit. We have now discovered that 4-1BB interacts with Galectin-9 (Gal-9), a member of a family of animal lectins that interact with proteins in part via carbohydrates. In functional studies of immune cells, and in disease models in vivo, we have found that Gal-9 is required for the activity of 4-1BB. We hypothesize that Gal-9 is a co-receptor protein for 4-1BB that enables 4-1BB monomers to complex into a functional signaling unit. We will determine the three dimensional structures of human 4-1BB complexed with Gal-9, and of 4-1BB complexed with 4-1BBL, using X-ray crystallography, and also attempt to crystallize a ternary complex of all three molecules. These studies will define a new paradigm for structural interaction in the TNFR family.
描述(由申请人提供):肿瘤坏死因子受体超家族(TNFSF/TNFRSF)中的蛋白质在免疫系统细胞以及非淋巴结构细胞如基质细胞、上皮细胞和内皮细胞上表达。它们在调节许多器官中的细胞间通讯方面具有广泛的活性。TNF家族分子具有带“夹心卷曲”结构的典型TNF同源结构域,并且TNFR家族分子含有可变数目的配体结合胞外富含半胱氨酸结构域(CRD)。TNFSF在很大程度上作为细胞表面或可溶性同源三聚体具有活性,并且迄今为止解决的11种相互作用的结晶复合物显示三聚体接合3个单独的TNFRSF单体。单个三聚体复合物是否足以用于细胞活化尚不清楚,但基础三聚体的寡聚体也可能需要形成以用于最大信号传导。每个TNFRSF如何形成功能性信号单元可能由于配体结构的变化以及它们如何被受体识别而不同。TNFSF三聚体已被细分为3组:常规/钟形、EF-二硫键连接/球形和发散/盛开的花状。这些结构已经被认为在结合它们在细胞膜上的配体时调节TNFRSF单体之间的间隔,这已经被理论上控制连接到信号转导途径的衔接子的细胞内募集。我们已经研究了4-1BBL(CD 137 L/TNFSF 9),这是最近结晶,并显示出发挥任何发散/盛开的花状TNFSF分子的最开放的结构。这表明它可能不能像其他TNFSF蛋白那样有效地聚集3个单体4-1BB(CD 137/TNFRSF 9)分子,或者可能不能有效地允许寡聚体形成。因此,4-1BBL可能需要额外的辅助受体蛋白来接合4-1BB以聚集成全功能的信号传导单元。我们现在已经发现4-1BB与半乳糖凝集素-9(Gal-9)相互作用,半乳糖凝集素-9(Gal-9)是部分通过碳水化合物与蛋白质相互作用的动物凝集素家族的成员。在免疫细胞的功能研究和体内疾病模型中,我们发现Gal-9是4-1BB活性所必需的。我们假设Gal-9是4-1BB的共受体蛋白,其使4-1BB单体复合成功能性信号单元。我们将使用X射线晶体学确定与Gal-9复合的人4-1BB和与4-1BBL复合的4 - 1BB的三维结构,并且还尝试使所有三种分子的三元复合物结晶。这些研究将为TNFR家族的结构相互作用定义一个新的范式。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael Croft其他文献
Michael Croft的其他文献
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{{ truncateString('Michael Croft', 18)}}的其他基金
A Treg cell-intrinsic CTLA4-PKC-eta signaling pathway mediating contact-dependent suppression of tumor immunity: A novel target for cancer immunotherapy
Treg 细胞固有的 CTLA4-PKC-eta 信号通路介导接触依赖性肿瘤免疫抑制:癌症免疫治疗的新靶点
- 批准号:
10531229 - 财政年份:2018
- 资助金额:
$ 8.85万 - 项目类别:
A Treg cell-intrinsic CTLA4-PKC-eta signaling pathway mediating contact-dependent suppression of tumor immunity: A novel target for cancer immunotherapy
Treg 细胞固有的 CTLA4-PKC-eta 信号通路介导接触依赖性肿瘤免疫抑制:癌症免疫治疗的新靶点
- 批准号:
10053328 - 财政年份:2018
- 资助金额:
$ 8.85万 - 项目类别:
A Treg cell-intrinsic CTLA4-PKC-eta signaling pathway mediating contact-dependent suppression of tumor immunity: A novel target for cancer immunotherapy
Treg 细胞固有的 CTLA4-PKC-eta 信号通路介导接触依赖性肿瘤免疫抑制:癌症免疫治疗的新靶点
- 批准号:
10310411 - 财政年份:2018
- 资助金额:
$ 8.85万 - 项目类别:
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