Structure and Function of Natural Killer Cell Receptors

自然杀伤细胞受体的结构和功能

• 批准号: 8471041
• 负责人: Roy A Mariuzza
• 金额: $ 31.41万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471041
• 关键词: Affinity; Attenuated; Back; Binding; Binding Sites; Biochemical; Cadherins; Cell membrane; Cell physiology; Cell-Mediated Cytolysis; Cells; Complex; Cytolysis; Data; Detection; Development; Discrimination; E-Cadherin; Equilibrium; Event; Goals; Histocompatibility Antigens Class I; Homologous Gene; Immune response; Immune system; Immunologic Monitoring; Inflammation; Integrins; Knowledge; Ligands; MHC Class I Genes; Malignant - descriptor; Measurement; Mediating; Modeling; Molecular; Molecular Conformation; Mouse Strains; Murid herpesvirus 1; Myelogenous; Myeloid Cells; NK Cell Activation; Natural Immunity; Natural Killer Cells; Natural killer triggering receptor; Nuclear; Orphan; Outcome; Pattern; Play; Process; Proteins; Relative (related person); Resistance; Roentgen Rays; Role; Signal Transduction; Site; Structure; Testing; Tissues; Tumor-Derived; Viral; Viral Cancer; Virus Diseases; X-Ray Crystallography; base; cancer cell; cell injury; cytotoxicity; functional outcomes; injured; insight; interest; molecular recognition; monocyte; mutant; neoplastic cell; novel; p80 natural killer cell receptor; pathogen; public health relevance; receptor; treatment strategy; tumor; tumorigenic

DESCRIPTION (provided by applicant): Natural killer (NK) cells are a fundamental component of innate immunity against tumors and virally infected cells. NK cell function is regulated by a dynamic balance between activating receptors that trigger NK cytolytic activity and inhibitory receptors that detect the lack of normal MHC class I (MHC-I) expression. The past few years have witnessed major advances in our understanding of NK cell function, including the discovery that Ly49 NK receptors not only interact with MHC-I on target cells (in trans), but also with MHC-I on the NK cell itself (in cis), the demonstration that mouse cytomegalovirus (MCMV) evades detection by NK cells by expressing an MHC-like decoy ligand (m157) for Ly49s, and the identification of novel, non-MHC ligands for the orphan NK receptors KLRG1, NKp80, and NKp30. We propose to establish the structural basis for each of these newly discovered NK receptor-ligand interactions using X-ray crystallography, and to correlate this information with analyses of NK cell function. Our objectives are: 1. Basis for Ly49 engagement of MHC-I in cis versus trans. By lowering the threshold for NK cell activation, cis interactions optimize discrimination between normal and diseased cells. Using the structure of a Ly49 receptor with its stalk region, we have constructed a model for cis-trans interactions that we will test at the cellular level through functional and biochemical analyses of structure-based Ly49 mutants. 2. Basis for direct recognition of a viral pathogen by Ly49 receptors. To compare the interaction of NK receptors with viral versus host ligands, we will determine structures of the MCMV protein m157 bound to Ly49I and Ly49H. 3. E-cadherin interactions with KLRG1 and integrin 1E27. The inhibitory receptor KLRG1 directs NK cytolysis against tumors that have lost E-cadherin expression. The structure of KLRG1 bound to E-cadherin suggests an oligomerization model for KLRG1-E-cadherin interactions and implies that E-cadherin can co-engage KLRG1 and 1E27. We will test the oligomerization and co-engagement hypotheses. 4. Basis for cellular cross-talk via the activating receptors NKp80 and AICL. The NKp80-AICL interaction not only promotes NK cell- mediated cytolysis of malignant myeloid cells, but is also crucial for the mutual activation of NK cells and monocytes at inflammation sites. To understand the recognition event underpinning this cross-talk, we will determine the structure of NKp80 bound to AICL. 5. Basis for recognition of BAT3, a tumor- derived nuclear factor, by the natural cytotoxicity receptor NKp30. Following its release from tumor cells, BAT3 binds to NKp30 and triggers NKp30-mediated cytotoxicity. As a nuclear factor, BAT3 defines a completely new class of NK receptor ligand. Moreover, its identification as a danger signal makes the NKp30-BAT3 interaction of special interest for understanding how the immune system recognizes damaged cells. We propose to determine the structure of BAT3 in complex with NKp30.

描述（由申请人提供）：天然杀伤（NK）细胞是对肿瘤和病毒感染细胞的先天免疫力的基本组成部分。 NK细胞功能受到触发NK溶细胞活性的激活受体和检测缺乏正常MHC I类（MHC-I）表达的抑制受体的动态平衡的调节。 The past few years have witnessed major advances in our understanding of NK cell function, including the discovery that Ly49 NK receptors not only interact with MHC-I on target cells (in trans), but also with MHC-I on the NK cell itself (in cis), the demonstration that mouse cytomegalovirus (MCMV) evades detection by NK cells by expressing an MHC-like decoy ligand (m157) for LY49S以及孤儿NK受体KLRG1，NKP80和NKP30的新型非MHC配体的鉴定。 我们建议使用X射线晶体学建立这些新发现的NK受体配体相互作用的结构基础，并将这些信息与NK细胞功能的分析相关联。 我们的目标是：1。LY49 MHC-I参与顺式与Trans的基础。 通过降低NK细胞激活的阈值，CIS相互作用优化了正常细胞和患病细胞之间的歧视。 使用LY49受体的结构及其茎区域，我们已经构建了一个用于顺式传播相互作用的模型，我们将通过基于结构的LY49突变体的功能和生化分析在细胞水平上测试。 2。通过Ly49受体直接识别病毒病原体的基础。 为了比较NK受体与病毒与宿主配体的相互作用，我们将确定与LY49I和LY49H结合的MCMV蛋白M157的结构。 3。E-钙粘蛋白与KLRG1和整合素1E27的相互作用。 抑制性受体KLRG1针对损失E-钙粘蛋白表达的肿瘤指导NK胞解。 与E-钙粘蛋白结合的KLRG1的结构提出了KLRG1-E-钙粘蛋白相互作用的寡聚模型，并暗示E-钙粘蛋白可以共同接合KLRG1和1E27。 我们将测试寡聚化和共同参与假设。 4。通过激活受体NKP80和AICL的细胞串扰基础。 NKP80-AICL相互作用不仅促进了NK细胞介导的恶性髓样细胞的胞得分，而且对于在炎症部位的NK细胞和单核细胞的相互激活也至关重要。 为了了解这一串扰的识别事件，我们将确定与AICL结合的NKP80的结构。 5。通过天然细胞毒性受体NKP30识别BAT3（肿瘤衍生的核因子）的基础。 从肿瘤细胞释放后，BAT3与NKP30结合，并触发NKP30介导的细胞毒性。 作为核因素，BAT3定义了全新的NK受体配体。 此外，它作为危险信号的识别使NKP30-BAT3相互作用具有特殊兴趣的相互作用，以了解免疫系统如何识别受损细胞。 我们建议确定与NKP30复合物中BAT3的结构。