Defining, studying, and targeting sulfated tyrosine residues of cell surface receptors for disease treatment

项目摘要 细胞表面受体蛋白酪氨酸O-硫化(PTS)在细胞外生物分子中起着至关重要的作用 决定各种细胞过程的相互作用，包括细胞黏附、白细胞运输、激素 活动和免疫反应。酪氨酸-硫酸盐受体也参与了多种 人类疾病。因此，PTS可能成为治疗人类癌症的重要药物靶点。 疾病。尽管我们对PTS的了解有了很大的进步，但我们目前对其生物学上的了解 重要性仍处于初级阶段。我们寻求填补的正是这一知识缺口。在一个方向上，我们将进行 全面和基于发现的硫代蛋白质组研究，这将为揭示整个 人类受体硫蛋白相互作用组，并确定与疾病相关的硫蛋白-蛋白质相互作用。在 第二个方向，我们试图确定PTS在趋化因子受体功能中的作用。趋化因子 信号是慢性炎症性疾病的中心，并参与许多人类的发育。 疾病。趋化因子受体的N-末端含有酪氨酸残基，可以被硫酸盐化成 不同程度(指定为“临时技术秘书处水平”)。我们的假设是趋化因子受体(可能还有其他 细胞表面受体)可以被硫酸盐化到不同的PTS水平，这允许受体结合 不同的配体并导致下游生物/病理事件的改变。除了基本的 在机理研究方面，我们还试图探索和开发针对PTS的新型治疗药物。 趋化因子受体，如C-X-C趋化因子受体4(CXCR4)。CXCR4在 在生理和病理条件下，它代表着药物开发的一个重要靶点。我们的 拟议的工作将通过三项技术突破来实现，包括工程 识别硫代酪氨酸的小蛋白支架，使用最先进的质谱学方法，以及 在哺乳动物细胞中编码硫代酪氨酸的遗传方法的发展。总的来说，成功的 拟议工作的完成预计将产生关于受体硫代蛋白质组的全面数据，以获得 对PTS相关细胞生物学的洞察，并产生人类新的治疗干预措施 疾病。

Project Summary Protein tyrosine O-sulfation (PTS) of cell surface receptors plays a crucial role in extracellular biomolecular interactions that dictate various cellular processes, including cell adhesion, leukocyte trafficking, hormone activities, and immune responses. Tyrosine-sulfated receptors also participate in the development of various human diseases. Accordingly, PTS could emerge as an important drug target for the treatment of human diseases. Despite substantial advances in our knowledge of PTS, our current understanding of its biological significance is still in its infancy. It is this knowledge gap we seek to fill. In one direction, we will conduct comprehensive and discovery-based sulfoproteomic studies, which will lay the foundation to unveil the entire human receptor sulfointeractome and to identify disease-related sulfoprotein-protein interactions. In the second direction, we seek to define the role of PTS in the function of chemokine receptors. Chemokine signaling is central to chronic inflammatory conditions and participates in the development of many human diseases. At their N-terminal region, chemokine receptors contain tyrosine residues that can be sulfated to different extent (designated as “PTS level”). Our hypothesis is that chemokine receptors (and possibly other cell surface receptors in general) can be sulfated to various PTS levels, which allows the receptors to bind different ligands and leads to altered downstream biological/pathological events. In addition to basic mechanistic studies, we also seek to explore and develop novel therapeutic agents targeting PTS of chemokine receptors, such as C-X-C chemokine receptor type 4 (CXCR4). CXCR4 plays important roles in both physiological and pathological conditions, and it represents a crucial target in drug development. Our proposed work will be enabled by three technological breakthroughs, including the engineering of sulfotyrosine-recognizing small protein scaffolds, the use of state-of-the-art mass spectrometry methods, and the development of genetic method to encode sulfotyrosine in mammalian cells. Overall, the successful completion of the proposed work is expected to yield comprehensive data on receptor sulfoproteome, to gain insights into PTS-associated cellular biology, and to produce novel therapeutic interventions of human diseases.