Molecular mechanisms for the evolution of the total peptide binding set in S100 proteins

S100 蛋白中总肽结合组进化的分子机制

• 批准号: 9320556
• 负责人: Michael Jonathan Harms
• 金额: $ 28.95万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320556
• 关键词: Address; Alpha Cell; Amino Acid Sequence; Amino Acids; Animals; Binding; Binding Proteins; Biochemical; Biological; Biological Process; Biology; Biophysical Process; Calcium; Cells; Coupled; Data; Disease; Environment; Evolution; Fingerprint; Gene Duplication; Goals; Heart Diseases; High-Throughput Nucleotide Sequencing; Human; In Vitro; Influentials; Light; Malignant Neoplasms; Measures; Modernization; Molecular; Mutation; Natural Selections; Orthologous Gene; Peptide Mapping; Peptides; Phage Display; Phylogenetic Analysis; Process; Property; Protein Fragment; Proteins; Recording of previous events; Role; S100 Proteins; Sampling; Signal Transduction; Signaling Protein; Specificity; Testing; Time; Tissue Extracts; Work; biophysical analysis; computer studies; deep sequencing; duplicate genes; experimental study; insight; member; protein function; reconstruction; response

PROJECT SUMMARY The long-term goal of this project is to understand the ability of the proteins S100A5 and S100A6 to bind to and recognize their target proteins. S100A5 and S100A6 are small proteins that bind to downstream target proteins in the cell in response to calcium; however, the precise targets remain poorly understood. S100A5 and S100A6 are both upregulated in disease states, including various cancers and heart disease; however, not knowing their binding partners hampers efforts to understand the causes or consequences of this effect. The first goal of the project is to identify possible binding targets using “phage display,” an approach for identifying short protein fragments that may bind to the protein. This approach, while powerful, is also plagued by false positive rates. To get around this, the project is guided by the words of a famous geneticist: “nothing in biology makes sense except in light of evolution.” This means that averaging phage display/binding results from the human proteins versus other animals amplifies the signal of biologically important protein fragments. The second goal is to identify the pieces on S100A5 and S100A6 that are important for its interactions with its possible targets. Revealing the evolutionary path by which a protein acquired its current protein targets efficiently reveals the residues responsible and thus sets up mechanistic studies of its binding.

项目摘要 该项目的长期目标是了解蛋白质S100 A5和S100 A6结合蛋白的能力。 并识别它们的靶蛋白。S100 A5和S100 A6是与下游靶点结合的小蛋白， 蛋白质在细胞中响应钙;然而，精确的目标仍然知之甚少。S100 A5和 S100 A6在疾病状态中均上调，包括各种癌症和心脏病;然而， 了解其具有约束力的伙伴妨碍了理解这种影响的原因或后果的努力。 该项目的第一个目标是使用“噬菌体展示”来鉴定可能的结合靶点， 鉴定可与所述蛋白质结合的短蛋白质片段。这种方法虽然强大， 被假阳性率所困扰为了解决这个问题，该项目以一位著名遗传学家的话为指导： “生物学中没有任何东西是有意义的，除非从进化的角度来看。”这意味着平均噬菌体展示/结合 人类蛋白质与其他动物蛋白质的对比结果放大了生物学上重要的蛋白质的信号 片段第二个目标是确定S100 A5和S100 A6上对其重要的部件， 与可能的目标之间的互动。揭示了蛋白质获得电流的进化路径 蛋白质靶标有效地揭示了负责的残基，从而建立了其结合的机理研究。