Latent TGF-β2 Structure and Activation
潜在 TGF-β2 结构和激活
基本信息
- 批准号:10586060
- 负责人:
- 金额:$ 70.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVActinsAffinityAntibodiesAortic AneurysmBindingBiochemicalBiologicalBiological ProcessBlood VesselsCardiovascular PhysiologyCardiovascular systemCell LineCell surfaceCellsChimeric ProteinsComplexCryoelectron MicroscopyCrystallizationCrystallographyCytoplasmic TailCytoskeletonDefectDetectionDevelopmentDimerizationDiseaseExtracellular MatrixFamilyFollow-Up StudiesFoundationsGrantGrowth FactorHeartHumanIntegral Membrane ProteinIntegrin BindingIntegrinsKnowledgeLRRC32 geneLengthLoeys-Dietz SyndromeMediatingMembraneModelingMolecular ChaperonesMolecular ConformationMucocutaneous Lymph Node SyndromeMusMutagenesisMutateMutationN-terminalPatientsPeptide HydrolasesPeptidesPhysiologicalPilot ProjectsPreparationProcessProtein SecretionRGD (sequence)RanaReagentResearchRoleSclerodermaSerine ProteaseShapesSiteStructureSystemic SclerodermaTestingTherapeuticTimeTissuesTransforming Growth Factor Beta 2Transforming Growth Factor betaTransforming Growth Factor beta ReceptorsVertebratesVirusX-Ray Crystallographycardiac repaircofactorcoronary fibrosisdimerdisulfide bondextracellularlatent TGF-beta binding proteinmembermonomernanobodiesnovelnovel therapeuticspreventreceptorrepairedtherapeutic target
项目摘要
Abstract. Transforming growth factor β2 (TGF-β2) is critically important for heart and vascular development
and repair. TGF-β2 dysregulation is seen in patient TGF-β2 mutations, systemic sclerosis, and Kawasaki
disease, which have cardiovascular sequelae such as aortic aneurysms and cardiac fibrosis. TGF-β1, 2 and 3
are synthesized as proproteins that dimerize and associate with milieu molecules that regulate TGF-β tissue
localization, such as the transmembrane protein glycoprotein A repetitions predominant (GARP) and latent
TGF-β binding proteins (LTBPs) in the extracellular matrix (ECM). Proconvertases cleave between the
prodomain and growth factor (GF) domain; however, the prodomain dimer remains non-covalently associated
with the GF in a proTGF-β–milieu molecule complex after secretion. ProTGF-β–milieu molecule complexes are
inactive because the prodomains encircle the GF and prevent binding to TGF-β receptors. ProTGF-β1 and 3
activation is mediated by binding of integrins αVβ6 and αVβ8 to an RGD-motif in the prodomain and requires
proTGF-β association with a milieu molecule. How proTGF-β2, which lacks an RGD-motif, is activated remains
a mystery. Aim 1 will define the structure of proTGF-β2 to understand its mechanism of latency. Aim 2 will
determine proTGF-β2/milieu molecule complex structures by X-ray crystallography and cryo-EM to define how
milieu molecules bind and alter TGF-β2 latency. We will generate antibodies to use as crystallization
chaperones in addition to using already developed nanobodies to proTGF-β2. Complementary unfolding
studies will test the hypothesis that milieu molecule binding stabilizes proTGF-β2. Aim 3 characterizes TGF-β2
activation. Follow-up studies will identify cell-lines that natively activate TGF-β2 and characterize the
physiologically relevant process. The results of this grant will enhance our understanding of TGF-β2 latency
and activation in extracellular milieus and lay the foundation for developing therapeutics that target proTGF-β2
and its physiologically relevant complexes with milieu molecules.
抽象的。转化生长因子β-2(转化生长因子-β-2)在心脏和血管发育中起重要作用
并进行修复。转化生长因子-β-2基因突变、系统性硬化症和川崎患者的转化生长因子-β-2基因异常
疾病,有心血管后遗症,如主动脉瘤和心脏纤维化。转化生长因子-β1、2和3
被合成为二聚体的前蛋白,并与调节转化生长因子-β组织的环境分子结合。
定位,如跨膜蛋白糖蛋白A重复占优势(GARP)和潜伏
细胞外基质中的转化生长因子-β结合蛋白(LTBP)。原转化酶分裂在
前结构域和生长因子(GF)结构域;然而,前结构域二聚体保持非共价关联
分泌后与生长因子形成原转化生长因子-β-环境分子复合体。前转化生长因子-β-环境分子复合体
无效是因为前结构域包围了GF,阻止了与转化生长因子-β受体的结合。转化生长因子原-β1和3
激活是通过整合素αVβ6和αVβ8与前域中的RGD基序结合而介导的,需要
前转化生长因子-β与环境分子的关系。缺乏β基序的原转化生长因子-RGD2是如何被激活的仍然存在
一个谜。目的1定义前转化生长因子-β2的结构,以了解其潜伏期的机制。目标2将
用X射线结晶学和低温电子显微镜测定前转化生长因子-β_2/环境分子复合体结构
环境分子结合并改变转化生长因子-β-2潜伏期。我们将产生抗体作为结晶
除了利用已经开发的纳米体来促进转化生长因子-β的伴侣外,2.互补的展开
研究将验证环境分子结合稳定前转化生长因子-β2的假设。
激活。后续研究将确定天然激活转化生长因子-β-2的细胞系,并表征
生理上相关的过程。这项资助的结果将加深我们对转化生长因子-β2潜伏期的理解
并在细胞外环境中激活,为开发靶向前转化生长因子-β-2的治疗药物奠定了基础
以及它与环境分子的生理相关的复合体。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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TIMOTHY A SPRINGER的其他文献
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{{ truncateString('TIMOTHY A SPRINGER', 18)}}的其他基金
Structural basis of von Willebrand factor biology and physics
冯维勒布兰德因子生物学和物理学的结构基础
- 批准号:
10198035 - 财政年份:2019
- 资助金额:
$ 70.65万 - 项目类别:
Structural basis of von Willebrand factor biology and physics
冯维勒布兰德因子生物学和物理学的结构基础
- 批准号:
10434710 - 财政年份:2019
- 资助金额:
$ 70.65万 - 项目类别:
Structures and Conformational Equilibria of Integrin alpha5 beta1
整合素α5β1的结构和构象平衡
- 批准号:
9079774 - 财政年份:2016
- 资助金额:
$ 70.65万 - 项目类别:
Structures and Conformational Equilibria of Integrin alpha5 beta1
整合素α5β1的结构和构象平衡
- 批准号:
9265127 - 财政年份:2016
- 资助金额:
$ 70.65万 - 项目类别:
Structural mechanisms underlying latency and activation of GDF8
GDF8 潜伏期和激活的结构机制
- 批准号:
9302311 - 财政年份:2016
- 资助金额:
$ 70.65万 - 项目类别:
Structural mechanisms underlying latency and activation of GDF8
GDF8 潜伏期和激活的结构机制
- 批准号:
9175103 - 财政年份:2016
- 资助金额:
$ 70.65万 - 项目类别:
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