CRYSTAL STRUCTURE OF THE NATURAL KILLER CELL RECEPTOR 2B4 IN COMPLEX WITH CD48

自然杀伤细胞受体 2B4 与 CD48 复合物的晶体结构

• 批准号: 7358950
• 负责人: Roy A Mariuzza
• 金额: $ 0.24万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7358950
• 关键词: CRYSTAL; STRUCTURE; NATURAL; KILLER; CELL

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As part of innate immunity, natural killer (NK) cells are capable of killing certain tumor and virally infected cells. A fine balance between the activating and inhibitory receptors on the cells surface controls the cytolytic activity of NK cells. The inhibitory receptors provide the protection from lysis by recognizing class I MHC molecules on healthy host cells. Activating NK receptors mediate the killing of tumor or virally infected cells through specific ligand recognition. In contrast to the inhibitory receptors, much less is known about the structures of activating NK receptors. 2B4, a transmembrane receptor expressed primarily on NK cells and on a subset of CD8+ T cells, plays an important role in activating NK-mediated cytotoxicity through its interaction with CD48 on target cells. 2B4 comprises two Ig-like extracellular domains (D1 and D2) and a cytoplasmic portion containing a CxC/+ motif that may bind a complementary CxxC/¿¿¿ motif in the linker for activation of T cells (LAT). In addition to LAT, the cytoplasmic tail of 2B4 binds the SH2 domain-containing protein SAP. This association is crucial for 2B4 to deliver activating signals to NK cells. Indeed, in the absence of SAP, 2B4 tranduces inhibitory signals that result in NK cell inactivation. The finding that 2B4 can both activate and inhibit NK cytolysis, combined with the identification of CD48 as its biological ligand, make 2B4 a compelling target for structural analysis.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。作为先天免疫的一部分，自然杀伤(NK)细胞能够杀死某些肿瘤和病毒感染的细胞。细胞表面的激活受体和抑制受体之间的微妙平衡控制着NK细胞的杀伤活性。抑制性受体通过识别健康宿主细胞上的I类MHC分子来提供防止裂解的保护。激活NK受体通过特异性配体识别介导对肿瘤或病毒感染细胞的杀伤。与抑制性受体相比，人们对激活NK受体的结构知之甚少。2B4是一种主要表达于NK细胞和CD8+T细胞亚群的跨膜受体，通过与靶细胞上的CD48相互作用，在激活NK介导的细胞毒作用中发挥重要作用。2B4包括两个Ig样胞外域(D1和D2)和一个细胞质部分，该部分包含一个CxC/+基序，该基序可能结合连接子中互补的CxxC/？基序以激活T细胞(LAT)。除LAT外，2B4的细胞质尾部还与含有SH2结构域的蛋白SAP结合。这种联系对于2B4向NK细胞传递激活信号至关重要。事实上，在没有SAP的情况下，2B4传递抑制信号，导致NK细胞失活。2B4可以激活和抑制NK细胞溶解，结合CD48作为其生物配体的发现，使2B4成为结构分析的一个引人注目的靶点。