The Molecular Mechanism of DR3-TRADD Pathway
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- 英文论文题名：The Molecular Mechanism of DR3-TRADD Pathway
- 论文作者：Yin Xueying ; Jin Tengchuan
- 英文论文作者：Yin Xueying ; Jin Tengchuan ; Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease ; School of Life Sciences and Medical Center ; University of Science and Technology of China
- 年：2016
- 作者机构：Institute of Immunology and The CAS Key Laboratory of Innate Immunity and Chronic Disease,School of Life Sciences and Medical Center,University of Science and Technology of China;
- 英文论文关键词：TNFRSF25 ; TRADD ; crystal structure
- 会议召开时间：2016-11-04
- 会议录名称：第十一届全国免疫学学术大会壁报交流集
- 英文会议录名称：Proceedings of 2016 CSI Congress on Immunology
- 语种：英文
- 分类号：R392
- 学会代码：IGMD
- 会议名称：第十一届全国免疫学学术大会
- 会议地点：中国安徽合肥
- 主办单位：中国免疫学会
- 学会名称：中国免疫学会
- 页数：1
- 文件大小：974k
- 原文格式：D
- 会议级别：全国
摘要
DR3(TNFRSF25),a member of the tumor necrosis factor receptor(TNFR) superfamily,is widely expressed on lymphocytes as a receptor of TNF family cytokine TL1A(TNFSF15).TL1A-DR3 pair can promote lymphocyte costimulation,mucosal hyperplasia and autoimmune inflammation through intracytoplasmic death domain and its adaptor protein TRADD(TNFR-associated death domain),which can further activate NFκB signaling pathway.Up-regulation of TL1 A is characteristic of a variety of human inflammatory diseases,including inflammatory bowel diseases Crone's disease and ulcerative colitis,rheumatoid arthritis and psoriasis,which are sensitive to TNF inhibition,though the mechanism remains unknown.Here we present 2.7 and 2.5 crystal structures of death domains of DR3 from both human and mouse.Mouse DR3 DD adopts a classical six-helix bundle structure while human DR3 DD displays a completely different and extended structure,which makes up hypothesize that h DR3 DD stands for activated-state while m DR3 DD stands for resting-state conformation.The open structure of h DR3 DD may be more accessible for DR3/TRADD DD binding.Extracellular ligand binding induced oligomerization of extracellular domain of DR3 may induce the conformation changes of its DD and simultaneously activate downstream signaling.But in resting-state,DR3 DD may remain in a self-inhibited m DR3 DDlike state.Our result shows a mechanistic switch model of DR3 activation,which allows NF-κB activation and inflammatory regulation.
DR3(TNFRSF25),a member of the tumor necrosis factor receptor(TNFR) superfamily,is widely expressed on lymphocytes as a receptor of TNF family cytokine TL1A(TNFSF15).TL1A-DR3 pair can promote lymphocyte costimulation,mucosal hyperplasia and autoimmune inflammation through intracytoplasmic death domain and its adaptor protein TRADD(TNFR-associated death domain),which can further activate NFκB signaling pathway.Up-regulation of TL1 A is characteristic of a variety of human inflammatory diseases,including inflammatory bowel diseases Crone's disease and ulcerative colitis,rheumatoid arthritis and psoriasis,which are sensitive to TNF inhibition,though the mechanism remains unknown.Here we present 2.7 and 2.5 crystal structures of death domains of DR3 from both human and mouse.Mouse DR3 DD adopts a classical six-helix bundle structure while human DR3 DD displays a completely different and extended structure,which makes up hypothesize that h DR3 DD stands for activated-state while m DR3 DD stands for resting-state conformation.The open structure of h DR3 DD may be more accessible for DR3/TRADD DD binding.Extracellular ligand binding induced oligomerization of extracellular domain of DR3 may induce the conformation changes of its DD and simultaneously activate downstream signaling.But in resting-state,DR3 DD may remain in a self-inhibited m DR3 DDlike state.Our result shows a mechanistic switch model of DR3 activation,which allows NF-κB activation and inflammatory regulation.
DR3(TNFRSF25),a member of the tumor necrosis factor receptor(TNFR) superfamily,is widely expressed on lymphocytes as a receptor of TNF family cytokine TL1A(TNFSF15).TL1A-DR3 pair can promote lymphocyte costimulation,mucosal hyperplasia and autoimmune inflammation through intracytoplasmic death domain and its adaptor protein TRADD(TNFR-associated death domain),which can further activate NFκB signaling pathway.Up-regulation of TL1 A is characteristic of a variety of human inflammatory diseases,including inflammatory bowel diseases Crone's disease and ulcerative colitis,rheumatoid arthritis and psoriasis,which are sensitive to TNF inhibition,though the mechanism remains unknown.Here we present 2.7 and 2.5 crystal structures of death domains of DR3 from both human and mouse.Mouse DR3 DD adopts a classical six-helix bundle structure while human DR3 DD displays a completely different and extended structure,which makes up hypothesize that h DR3 DD stands for activated-state while m DR3 DD stands for resting-state conformation.The open structure of h DR3 DD may be more accessible for DR3/TRADD DD binding.Extracellular ligand binding induced oligomerization of extracellular domain of DR3 may induce the conformation changes of its DD and simultaneously activate downstream signaling.But in resting-state,DR3 DD may remain in a self-inhibited m DR3 DDlike state.Our result shows a mechanistic switch model of DR3 activation,which allows NF-κB activation and inflammatory regulation.
引文