Sulfotyrosine, an essential determinant for diverse protein-protein interactions

磺基酪氨酸，多种蛋白质-蛋白质相互作用的重要决定因素

• 批准号: 10545692
• 负责人: PAMELA C RONALD
• 金额: $ 46.81万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545692
• 关键词: Address; Affinity; Agriculture; Animals; Antigen-Antibody Complex; Area; Awareness; Bacteria; Binding; Biological Assay; Biological Process; Cardiovascular Diseases; Cell surface; Cells; Coagulation Process; Complex; Development; Engineering; Foundations; Goals; HIV; Health; Human; Immune; Immune response; Knowledge; Ligand Binding; Medicine; Modification; Peptides; Phenotype; Plants; Play; Positioning Attribute; Process; Proteins; Reagent; Research; Role; Signal Transduction; Specificity; Spectrometry; Sulfate; Ticks; United States National Institutes of Health; Yeasts; blood treatment; gene discovery; insight; microorganism interaction; mutant; novel; protein protein interaction; receptor; response; therapeutic evaluation; tool; tyrosine O-sulfate; whole genome

1 This MIRA project will advance understanding of the function of tyrosine sulfation, a fundamental 2 modification that regulates diverse biological functions. For example, sulfation plays a critical role 3 in entry of HIV into human cells, in the interaction of microbial molecules with host immune 4 receptors and in the activity of tick-derived peptides, which hold potential for treatment of blood 5 clotting associated with cardiovascular diseases. Despite the increasing awareness of the 6 importance of tyrosine sulfation, most sulfated peptide complexes have not yet been fully 7 characterized. Further, we have only a partial view of the components essential for transducing 8 the response of such activated complexes. We also have limited strategies for efficiently 9 producing and testing the therapeutic potential of sulfated molecules. The PI is well positioned to 10 address these challenges. With support from the NIH, the PI discovered the host XA21 immune 11 receptor, a protein that is representative of a large class of plant and animal receptors. Further, 12 the PI's team isolated and characterized a sulfated peptide secreted by a Gram-negative 13 bacterium that binds to the XA21 receptor and activates the immune response. We propose 14 research in three related areas: We will isolate and characterize the diversity of receptors that 15 bind sTyr peptides, identify and analyze sTyr binding interfaces and pioneer a strategy to produce 16 novel sulfated molecules in an efficient manner. To accomplish our goals, we will employ new 17 experimental tools and approaches. These include use of established whole genome sequenced 18 mutant lines to rapidly assess phenotypes of newly discovered genes, sensitive assays to assess 19 ligand binding, state-of-the-art mass yeast cell surface display and spectrometry approaches to 20 engineer receptors and identify key components of immune complexes. The knowledge gained 21 from this research will provide new insights into an essential biological process, laying the 22 foundation for the development of reagents capable of inhibiting or activating cellular interactions 23 with a high degree of affinity and specificity with potential applications in research, agriculture and 24 medicine.

1这个MIRA项目将提高人们对酪氨酸硫酸盐功能的理解，这是一个基本的 2调节多种生物学功能的修改。例如，硫酸起着至关重要的作用 3在微生物分子与宿主免疫的相互作用中，HIV进入人类细胞中 4个受体和tick衍生肽的活性，有可能治疗血液 5与心血管疾病有关的凝结。尽管对 6酪氨酸硫酸化的重要性，大多数硫化肽复合物尚未完全 7特征。此外，我们只能对转换必不可少的组件有部分视图 8这种活化的复合物的响应。我们也有有限的策略来有效 9产生和测试硫化分子的治疗潜力。 PI的位置很好 10解决这些挑战。在NIH的支持下，PI发现了宿主XA21免疫 11受体，一种代表大型动植物受体的蛋白质。更远， 12 PI的团队孤立并描述了由革兰氏阴性剂分泌的硫酸肽 13与XA21受体结合并激活免疫反应的细菌。我们建议 14在三个相关领域的研究：我们将隔离并表征受体的多样性 15绑定Styr肽，识别和分析Styr结合界面，并开拓生产的策略 16新颖的硫化分子以有效的方式。为了实现我们的目标，我们将采用新的 17种实验工具和方法。这些包括使用已建立的整个基因组测序 18个突变线以快速评估新发现的基因的表型，评估敏感测定法 19配体结合，最先进的质量酵母细胞表面显示和光谱法 20工程师受体并确定免疫复合物的关键成分。知识获得了 21这项研究将为基本生物学过程提供新的见解 22开发能够抑制或激活细胞相互作用的试剂的基础 23具有高度的亲和力和特异性，与潜在的研究，农业和农业和 24药物。