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

项目摘要 细胞表面受体的蛋白质酪氨酸O-硫酸化（PTS）在细胞外生物分子中起着重要作用 决定各种细胞过程的相互作用，包括细胞粘附、白细胞运输、激素 活动和免疫反应。酪氨酸硫酸化受体也参与各种 人类疾病。因此，PTS可能成为治疗人类肿瘤的重要药物靶点 疾病尽管我们对PTS的认识有了很大的进步，但我们目前对它的生物学特性的理解， 重要性仍处于初期阶段。这就是我们要填补的知识空白。在一个方向，我们将进行 全面的和基于发现的磺基蛋白质组学研究，这将奠定基础，揭开整个 人受体磺基相互作用组和鉴定疾病相关的磺基蛋白-蛋白相互作用。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。化因子 信号传导是慢性炎性病症的中心，并参与许多人类疾病的发展。 疾病在它们的N-末端区域，趋化因子受体含有酪氨酸残基，其可以被硫酸化， 不同程度（指定为“临时技术秘书处级别”）。我们的假设是，趋化因子受体（可能还有其他 细胞表面受体）可以硫酸化到各种PTS水平，这使得受体能够结合 不同的配体，并导致改变下游生物/病理事件。除了基本 机制的研究，我们还寻求探索和开发新的治疗药物靶向PTS的 趋化因子受体，如C-X-C趋化因子受体4型（CXCR 4）。CXCR 4在以下方面发挥着重要作用： 在生理和病理条件下，它代表了药物开发中的关键目标。我们 拟议的工作将通过三项技术突破实现，包括 磺基酪氨酸识别小蛋白支架，使用最先进的质谱法，和 哺乳动物细胞中编码磺基酪氨酸的遗传方法的发展。总的来说，成功 完成拟议的工作，预计将产生全面的数据受体磺基蛋白质组，以获得 深入了解PTS相关的细胞生物学，并产生新的人类治疗干预措施， 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.