Conformational regulation in integrin bidirectional transmembrane signaling
整合素双向跨膜信号传导的构象调控
基本信息
- 批准号:9130426
- 负责人:
- 金额:$ 41.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:Adaptor Signaling ProteinAddressAdhesionsAdhesivesAdverse effectsAffectAffinityAgonistBindingBiological ProcessBiologyBlood PlateletsCell Surface ReceptorsCell SurvivalCell membraneCellsClinicalClinical TrialsClot retractionCysteineCytoplasmic TailDevelopmentDistalDisulfidesDrosophila genusDrug usageElectronsEpitopesExtracellular DomainFaceFamilyFibrinogenFluorescenceGoalsHealthHemostatic functionHumanImmuneImmune responseIntegrin BindingIntegrin InhibitionIntegrinsLabelLaboratoriesLengthLeukocytesLigand BindingLigandsMalignant NeoplasmsMediatingMembraneModelingMolecularMolecular ConformationMutagenesisPharmaceutical PreparationsPlayProcessProtein BindingProtein IsoformsProteinsRGD (sequence)RegulationRestRoleScanningSignal TransductionStructureSupporting CellSurfaceTailTalinThrombocytopeniaThrombosisTransmembrane DomainTreatment EfficacyTumor AngiogenesisWorkbasecell motilitycell typecrosslinkdesignextracellularflexibilityimprovedinhibitor/antagonistmanmimeticsnovelnovel strategiesnovel therapeuticsorgan growthresponsetransmission processtumor growth
项目摘要
DESCRIPTION (provided by applicant): Integrins are α/ß heterodimeric cell surface receptors that, via their ability to exist in multiple conformations, regulate a diverse array of biological processes ranging from organ development to immune regulation to hemostasis. Proteins binding to either the extracellular or cytoplasmic face of an integrin can effect long-range conformational changes that are transmitted across the plasma membrane. Bi-directional signal transmission from outside to inside initiates cell signaling cascades supporting cell migration and survival, while binding of specific proteins to the cytoplasmic tails of the integrin (inside-ot signaling) induces long-range conformational rearrangements within the ectodomains that convert it from a resting to an activated (ligand-binding) competent state. Despite many studies over the past 25 years, exactly how inside-out and outside-in signaling is controlled through the transmembrane and cytoplasmic domains are still not understood at the structural level. Development of novel therapeutics free of confounding side effects requires an atomic level molecular understanding of these processes. We recently found that deleting the C-terminus of the α-subunits in integrins, including the platelet αIIbß3 and leukocyte aLß2, has a dramatic ad unexpected effect on the ability of integrins to undergo conformational change in response to inside-out signals. Aim 1 of this proposal will focus on defining this novel role of integrin a-subunit cytoplasmic domains, especially their less-conserved membrane distal region, in regulating integrin inside-out activation. Multiple independent approaches, including comprehensive mutagenesis, cysteine scanning accessibility, disulfide crosslinking, and cysteine fluorescence labeling of full-length integrins, will be employed to examine restructuring of integrin transmembrane and cytoplasmic domains in response to inside-out and outside-in signaling in coordination with the multiple active conformations of the ectodomain. Aim 2 will focus on a second important issue: namely, the observation that most RGD (Arg-Gly-Asp)-mimetic integrin antagonists in clinical trials or in clinical use for treating thrombosis or cance have the undesirable side effect of inducing thrombocytopenia and in some cases, thrombosis or enhanced tumor growth and angiogenesis. These effects appear to be due to drug-induced conformational changes leading to integrin activation and creation of neo-epitopes capable of inducing an immune response. Building on our recent structural studies, we will define at the atomic level the critical structural changes that take place when an integrin binds either small or
large ligands. Findings made will be used to guide the development of novel integrin antagonists that block function without altering integrin conformation. Together, these complementary Specific Aims will reveal the molecular basis for ligand-induced integrin conformational change and provide the structure-based understanding of bidirectional integrin signaling necessary to facilitate development of novel integrin antagonists with potentially improved therapeutic efficacy.
描述(申请人提供):整合素是α/?异二聚体细胞表面受体,通过其以多种构象存在的能力,调节从器官发育到免疫调节到止血的各种生物学过程。结合到整合素胞外或细胞质表面的蛋白质可以影响通过质膜传递的长期构象变化。从外到内的双向信号传递启动了支持细胞迁移和生存的细胞信号级联反应,而特定蛋白与整合素的细胞质尾部结合后,在胞外区域内诱导了长距离的构象重排,将其从静止状态转变为激活的(配体结合)活性状态。尽管在过去的25年里进行了许多研究,但在结构水平上仍不清楚自内向外和由外向内的信号是如何通过跨膜和细胞质结构域控制的。开发没有混杂副作用的新疗法需要对这些过程的原子水平的分子理解。我们最近发现,删除整合素中α-亚基的C-末端,包括血小板αIIbü3和白细胞α2,对整合素的构象变化能力有显著的意外影响。该提案的目的1将集中于确定整合素a亚单位胞质结构域,特别是其保守程度较低的膜远端区域,在调节整合素由内向外激活中的这一新作用。多种独立的方法,包括全面的突变、半胱氨酸扫描可及性、二硫键交联和半胱氨酸全长整合素的荧光标记,将被用来研究整合素跨膜和胞质结构域与胞外结构域的多种活性构象相协调的由内向外和由外向内信号的重组。目的2将重点放在第二个重要的问题上:即,观察到大多数临床试验或临床用于治疗血栓或癌症的RGD(Arg-Gly-Asp)类整合素拮抗剂都有导致血小板减少的不良副作用,在某些情况下,血栓形成或促进肿瘤生长和血管生成。这些效应似乎是由于药物诱导的构象变化导致整合素的激活和能够诱导免疫反应的新表位的产生。在我们最近的结构研究的基础上,我们将在原子水平上定义当整合素与小分子或小分子结合时发生的关键结构变化
大的配体。这些发现将用于指导新型整合素拮抗剂的开发,这些拮抗剂可以在不改变整合素构象的情况下阻断功能。总之,这些互补的特异性靶点将揭示配体诱导的整合素构象变化的分子基础,并提供对双向整合素信号的基于结构的理解,这对于开发具有潜在改善治疗效果的新型整合素拮抗剂是必要的。
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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Jieqing Zhu其他文献
Jieqing Zhu的其他文献
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{{ truncateString('Jieqing Zhu', 18)}}的其他基金
Structural Mechanisms Underlying the Activity Regulation of the Receptor-like Protein Tyrosine Phosphatase, CD148/PTPRJ
受体样蛋白酪氨酸磷酸酶 CD148/PTPRJ 活性调节的结构机制
- 批准号:
10609869 - 财政年份:2020
- 资助金额:
$ 41.75万 - 项目类别:
Structural Mechanisms Underlying the Activity Regulation of the Receptor-like Protein Tyrosine Phosphatase, CD148/PTPRJ
受体样蛋白酪氨酸磷酸酶 CD148/PTPRJ 活性调节的结构机制
- 批准号:
10391480 - 财政年份:2020
- 资助金额:
$ 41.75万 - 项目类别:
Structural Mechanisms Underlying the Activity Regulation of the Receptor-like Protein Tyrosine Phosphatase, CD148/PTPRJ
受体样蛋白酪氨酸磷酸酶 CD148/PTPRJ 活性调节的结构机制
- 批准号:
10387407 - 财政年份:2020
- 资助金额:
$ 41.75万 - 项目类别:
Structural Transition of Cellular Integrins and Applications Thereof
细胞整合素的结构转变及其应用
- 批准号:
10441416 - 财政年份:2016
- 资助金额:
$ 41.75万 - 项目类别:
Structural Transition of Cellular Integrins and Applications Thereof
细胞整合素的结构转变及其应用
- 批准号:
10666370 - 财政年份:2016
- 资助金额:
$ 41.75万 - 项目类别:
Structural Transition of Cellular Integrins and Applications Thereof
细胞整合素的结构转变及其应用
- 批准号:
9248410 - 财政年份:2016
- 资助金额:
$ 41.75万 - 项目类别:
Structural Transition of Cellular Integrins and Applications Thereof
细胞整合素的结构转变及其应用
- 批准号:
10052843 - 财政年份:2016
- 资助金额:
$ 41.75万 - 项目类别:
Structural Transition of Cellular Integrins and Applications Thereof
细胞整合素的结构转变及其应用
- 批准号:
10198990 - 财政年份:2016
- 资助金额:
$ 41.75万 - 项目类别:
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