ANALYSIS OF TYROSINE SULFATION: HIV

酪氨酸硫酸化分析：HIV

• 批准号: 7956091
• 负责人: HUGH B NICHOLAS
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956091
• 关键词: Affinity; Animals; Binding; Binding Sites; Biochemical; Biological; Biomedical Research; Cells; Characteristics; Charge; Cholecystokinin; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Cytokine Receptors; Enzymes; Exhibits; Family; Funding; Gastrointestinal tract structure; Glycoproteins; Golgi Apparatus; Grant; HIV; HIV-1; High Performance Computing; Hormone Receptor; Immune; Infection; Inorganic Sulfates; Institution; Ligands; Location; Neuraxis; Paper; Peptide Receptor; Peptides; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Proteins; Rat Protein; Research; Research Personnel; Resources; Role; Side; Site; Source; Substrate Specificity; System; Tail; Testing; Tissues; Tyrosine; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Virus; base; extracellular; peptide hormone; pressure; protein-tyrosine sulfotransferase; receptor; receptor binding; sulfation

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. This collaboration has been a broadly based examination of tyrosine sulfation, a widespread posttranslational modification of proteins and peptide hormones that pass through the Golgi system of animal cells. When the project began it was limited to a number of the peptide hormones involved in the digestive process and some, for example Cholecystokinin (CCK), active both in the gastrointestinal tract and in the central nervous system. The two tissues express different but closely related receptors. The tyrosine sulfation posttranslational modification has been estimated to occur to about one percent of tyrosine residues in Rat proteins. Our initial papers focused on finding and testing rules that could be used to accurately predict tyrosine sulfation sites (1,2,3). These initial studies led to the conclusions that tyrosylprotein sulfotransferase, the enzyme that catalyzes the sulfation of tyrosine residues in proteins and peptides, has a relatively low substrate specificity and is likely to modify any tyrosine residue that is sufficiently exposed and is near negatively charged side chains. Recently it has been discovered that tyrosine sulfation of specific cytokine receptors molecules is an essential requirement for some modes of infection of the HIV-1 virus and increases the efficiency of other modes of infection (5). Additionally, tyrosine sulfation has been shown to be required for the activity of some subfamilies within the glycoprotein hormone receptors family and seems to play a similar role in other subfamilies (6). Thus we have been exploring the possibility that other receptor families may require tyrosine sulfation for either effective or full activity. We have been correlating our predictions of tyrosine sulfation binding sites with additional biochemical information about the location of receptor binding site within the protein chain. We predict that 49 tyrosines of 32 seven-transmembrane peptide receptors are sulfated. Although we did not incorporate characteristics of confirmed sulfation sites such as clustering and conservation across species into our profile (Position Specific Scoring Matrix, PSSM), our predicted sites nevertheless exhibited these characteristics. The observed conservation suggests that there are strong evolutionary pressures to preserve selected biological activity of seven-transmembrane peptide receptors. The predicted tyrosine sulfation sites predominantly occur in the extracellular tail and extracellular loop 2, regions consistent with their association with binding pockets of the receptor (4). Post-translational modification of proteins by tyrosine sulfation enhances the affinity of extracellular ligand-receptor interactions important in the immune

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 这种合作一直是对酪氨酸硫酸化的广泛研究， 蛋白质和肽激素的广泛翻译后修饰 通过动物细胞的高尔基体系统。 当项目开始时 仅限于涉及消化的许多肽激素 过程，有些，例如胆囊动蛋白（CCK），都活跃在 胃肠道和中枢神经系统。 两组 表达不同但密切相关的受体。 酪氨酸硫酸盐 据估计，翻译后修改发生约1％ 大鼠蛋白中的酪氨酸残基。 我们最初的论文重点是查找 以及可用于准确预测酪氨酸硫酸盐的测试规则 站点（1,2,3）。 这些最初的研究得出了结论 酪蛋白亚硫蛋白硫代转移酶，催化硫化的酶 蛋白质和肽中的酪氨酸残基，具有相对较低的底物 特异性，很可能会修改任何充分的酪氨酸残留物 暴露并接近带负电的侧链。 最近，已经发现特异性细胞因子的酪氨酸硫酸化 受体分子是某些感染模式的必不可少的要求 HIV-1病毒并提高其他感染模式的效率（5）。 此外，已经证明酪氨酸硫酸化是活性所必需的 糖蛋白激素受体家族中的某些亚家族 在其他亚家族中扮演类似的角色（6）。 因此我们一直在探索 其他受体家族可能需要酪氨酸硫酸盐的可能性 有效或完整的活动。 我们一直在关联我们的预测 酪氨酸硫酸盐结合位点，以及有关其他生化信息 受体结合位点在蛋白质链中的位置。 我们预测，32个七种跨膜肽受体的49种酪氨酸是 硫化。尽管我们没有合并确认的特征 硫化位点，例如跨物种的聚类和养护， 配置文件（位置特定评分矩阵，PSSM），我们的预测站点 然而，表现出这些特征。观察到的保护 表明有强大的进化压力可以保留所选的 七跨膜肽受体的生物学活性。预测 酪氨酸硫酸盐位点主要发生在细胞外尾巴和 细胞外环2，区域与它们与结合的关联一致 受体的口袋（4）。 通过酪氨酸硫酸对蛋白质的翻译后修饰可增强 细胞外配体 - 受体相互作用的亲和力在免疫中很重要