Mechanisms of Smoothened Activation in Hedgehog Signaling
Hedgehog 信号传导平滑激活机制
基本信息
- 批准号:10552682
- 负责人:
- 金额:$ 32.3万
- 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:2022-02-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AdultBasal cell carcinomaBindingBinding SitesBiochemicalBiochemistryBiophysicsBrainCellsChildhoodCholesterolCommunicationComplexCryoelectron MicroscopyDataDevelopmentErinaceidaeExtracellular DomainFoundationsGenetic TranscriptionHumanIn VitroIntegral Membrane ProteinLinkLipid BindingLipidsMalignant NeoplasmsMass Spectrum AnalysisMembraneModelingMolecularMolecular ConformationMutagenesisNMR SpectroscopyOrganismPathway interactionsPatternPharmaceutical PreparationsPhysiologicalPredispositionPublishingRegenerative MedicineRegulationRepressionResearchResistanceResolutionSignal PathwaySignal TransductionSignal Transduction PathwaySiteSkin CarcinomaSterolsStructureTherapeuticTissuesTransmembrane DomainUrochordataX-Ray Crystallographyantagonistbody systemdesignhedgehog signal transductioninhibitorinsightmedulloblastomamolecular dynamicsnanobodiesprogramsresistance mechanismsmoothened signaling pathwaystructural biologytumor
项目摘要
PROJECT SUMMARY/ABSTRACT
MECHANISMS OF SMOOTHENED ACTIVATION IN HEDGEHOG SIGNALING. The Hedgehog (Hh) signaling
pathway coordinates development in humans and most metazoans. In adult tissues, aberrant Hh pathway
activation drives various cancers, including basal cell carcinoma of the skin and pediatric brain
medulloblastoma. An unusual mechanism enables Hh signal transduction. In the basal state, the transporter-
like molecule Patched1 (PTCH1) represses Smoothened (SMO), a seven-transmembrane protein. Hh inhibits
PTCH1, which unleashes SMO activity causing downstream transcription. A leading mechanistic hypothesis is
that cellular sterols activate SMO, but are sequestered by PTCH1 in the absence of Hh. Connecting the
putative transport function of PTCH1 to SMO activation remains one of the central mysteries in understanding
how the Hh signal is transduced across the membrane. A critical gap is how, and which, sterols directly
influence SMO activation. This proposal will address these questions in two aims. The first aim focuses on
which sterols activate SMO. Here, we will combine biochemistry, structural biology, and signaling studies to
define which sterols can activate SMO and how they do so. In the second aim, we focus on how sterol binding
to distinct sites on SMO influences Hh pathway activity. We will use X-ray crystallography, cryo-electron
microscopy, and NMR spectroscopy to generate an integrated high-resolution perspective on where sterols
bind to SMO, and how they influence SMO activity. These studies will provide a mechanistic picture on how the
Hh signal is transduced across the membrane. Such insights may enable the design of SMO inhibitors less
susceptible to tumor resistance or Hh pathway modulators for regenerative medicine.
项目总结/摘要
刺猬信号的平滑激活机制。Hedgehog(Hh)信号
在人类和大多数后生动物中协调发育。在成体组织中,异常的Hh通路
激活导致各种癌症,包括皮肤基底细胞癌和小儿脑
髓母细胞瘤一种不寻常的机制使Hh信号转导。在基础状态下,转运蛋白-
类似分子Patched 1(PTCH 1)抑制Smoothened(SMO),一种七跨膜蛋白。Hh抑制
PTCH 1,释放SMO活性,引起下游转录。一个主要的机械假说是
细胞固醇激活SMO,但在没有Hh的情况下被PTCH 1隔离。连接
PTCH 1对SMO激活的假定转运功能仍然是理解中的中心谜团之一
Hh信号是如何跨膜传递的一个关键的差距是如何,以及哪些,甾醇直接
影响SMO激活。本提案将从两个方面解决这些问题。第一个目标是
哪种固醇激活SMO。在这里,我们将结合联合收割机生物化学,结构生物学和信号研究,
定义哪些固醇可以激活SMO以及它们如何激活SMO。在第二个目标中,我们专注于甾醇如何结合
SMO上的不同位点影响Hh途径活性。我们会用X射线晶体学低温电子学
显微镜和核磁共振光谱,以产生一个综合的高分辨率的角度来看,甾醇
与SMO结合,以及它们如何影响SMO活性。这些研究将提供一个机械图片如何
Hh信号通过膜传导。这些见解可能使SMO抑制剂的设计更少
对肿瘤抗性敏感或用于再生医学的Hh通路调节剂。
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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Aashish Manglik其他文献
Aashish Manglik的其他文献
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{{ truncateString('Aashish Manglik', 18)}}的其他基金
Mechanisms of Smoothened Activation in Hedgehog Signaling
Hedgehog 信号传导平滑激活机制
- 批准号:
10365068 - 财政年份:2022
- 资助金额:
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Enhancing olfactory receptor expression for biochemical studies of odorant-receptor interactions
增强嗅觉受体表达以进行气味受体相互作用的生化研究
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10465009 - 财政年份:2022
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