Structural studies of gasdermin E and its recognition by caspase-3.
Gasdermin E 的结构研究及其被 caspase-3 识别。
基本信息
- 批准号:10571048
- 负责人:
- 金额:$ 8.05万
- 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:2022-11-03 至 2024-10-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptedApoptosisApoptoticAutoimmune DiseasesBacterial InfectionsBindingBiochemicalBiological AssayCASP1 geneCASP3 geneCaspaseCell DeathCell membraneCellular biologyComplexCrohn&aposs diseaseCrystallizationCrystallographyDataDefense MechanismsDevelopmentE proteinEpithelial CellsExtravasationFamilyFamily memberHost DefenseHumanImmuneInflammasomeInflammatoryInjury to KidneyKnowledgeLengthLiposomesLyticMediatingMembraneMolecularMolecular ConformationMucositisMusMutagenesisPathogenesisPeptide HydrolasesPeptidesPlayReagentReportingRestRoleSignal PathwaySiteStructureTechniquesTestingVirus DiseasesX ray diffraction analysisX-Ray Crystallographycytokineenzyme substrate complexinhibitorinsightintestinal epitheliumkidney fibrosismembermembrane assemblymicrobialpreventrecruitsuccesstissue injuryuptake
项目摘要
Abstract
The canonical and noncanonical inflammasome signaling pathways can induce pyroptosis and secretion of
inflammatory cytokines, which function as crucial immune defense mechanisms in microbial killing and
clearance. Pyroptosis is a type of regulated lytic cell death that is mediated by members of the gasdermin family
that assemble membrane pores upon cleavage by proteases. Gasdermin E (GSDME) can be cleaved by
apoptotic caspases-3 and 7, which then triggers plasma membrane pore formation and pyroptosis instead of
apoptosis. GSDME-mediated pyroptosis and cytokine release play crucial roles in host defense against viral or
bacterial infections. On the other hand, GSDME in intestinal epithelial cells has been implicated in mucosal
inflammation and pathogenesis of Crohn’s disease, and GSDME-mediated pyroptosis contributes to renal
fibrosis and kidney injury. Despite recent progress in our understanding of the recruitment and recognition of
gasdermin D (GSDMD) by inflammatory caspases, the molecular mechanisms of GSDME recognition and
cleavage by apoptotic caspases have been poorly defined. This proposal aims to address the critical gaps in our
knowledge using complementary structure-function approaches. We hypothesize that inactive GSDME is
maintained in an autoinhibited conformation through intramolecular amino-terminal domain (NTD)-carboxy-
terminal domain (CTD) interactions, which is recognized by apoptotic caspase-3 that cleaves at the NTD-CTD
linker region to release the autoinhibition. This study will explore the structural mechanisms of GSDME
autoinhibition and its recognition by caspase-3 to test the above hypothesis. The following specific aims are built
on our past and ongoing studies on gasdermins and pyroptosis. Aim 1 will characterize the molecular
mechanisms of GSDME autoinhibition. Our preliminary data show that GSDME protein can be crystallized and
the crystals diffracted X-ray well. We will determine the structure of GSDME at its autoinhibitory state using
crystallographic approaches, and validate the NTD-CTD interface through mutagenesis studies of the interface
residues using LDH release, PI uptake, and liposome leakage assays. Aim 2 will define the mechanisms of
GSDME recognition by caspase-3. We will probe the interaction between GSDME and caspase-3 through
biochemical and cell biology techniques, and determine the structure of GSDME in complex with caspase-3
using X-ray crystallography. The success of this proposal will not only reveal important insights into GSDME
autoinhibition and recognition by apoptotic caspases that move the field forward, but also facilitate the
development of specific inhibitors for apoptotic caspase-3 based on the distinct GSDME-caspase-3 interface,
which may be valuable reagents in the study of both pyroptosis and apoptosis signaling pathways.
摘要
项目成果
期刊论文数量(0)
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Tsan Sam Xiao其他文献
132 : Sensing of DNA by innate immune receptors
- DOI:
10.1016/j.cyto.2013.06.135 - 发表时间:
2013-09-01 - 期刊:
- 影响因子:
- 作者:
Tengchuan Jin;Jiansheng Jiang;Patrick Smith;Tsan Sam Xiao - 通讯作者:
Tsan Sam Xiao
Tsan Sam Xiao的其他文献
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{{ truncateString('Tsan Sam Xiao', 18)}}的其他基金
Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
- 批准号:
10024454 - 财政年份:2020
- 资助金额:
$ 8.05万 - 项目类别:
Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
- 批准号:
10654580 - 财政年份:2020
- 资助金额:
$ 8.05万 - 项目类别:
Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
- 批准号:
10441356 - 财政年份:2020
- 资助金额:
$ 8.05万 - 项目类别:
Molecular mechanisms of gasdermin recognition by proteases and autophagy proteins in cytokine release
细胞因子释放中蛋白酶和自噬蛋白识别gasdermin的分子机制
- 批准号:
10223159 - 财政年份:2020
- 资助金额:
$ 8.05万 - 项目类别:
Mechanisms of tunable posttranslational control of T-cell homeostasis and tolerance
T 细胞稳态和耐受性的可调节翻译后控制机制
- 批准号:
10410503 - 财政年份:2019
- 资助金额:
$ 8.05万 - 项目类别:
Mechanisms of tunable posttranslational control of T-cell homeostasis and tolerance
T 细胞稳态和耐受性的可调节翻译后控制机制
- 批准号:
10631929 - 财政年份:2019
- 资助金额:
$ 8.05万 - 项目类别:
Molecular mechanisms of gasdermins and pyroptosis
Gasdermin 和细胞焦亡的分子机制
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10112920 - 财政年份:2018
- 资助金额:
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Developing chemical probes that target specific inflammasomes
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$ 8.05万 - 项目类别:
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