一种重要急性期蛋白的构效耦合及演化机制研究

序列、结构和功能演变之间的关联是蛋白质进化的中心问题，但在其中发挥主导作用的究竟是“结构约束”还是“功能约束”尚有较大争议。C-反应蛋白（C-reactive protein, CRP）是一种重要的人类急性期蛋白，序列和结构在进化中高度保守，而表达模式却有显著的物种间差异，提示存在独特的构效耦合机制。我们的预实验发现，是否可变构展示“隐藏活性”，可能是CRP适配不同物种表达模式、确保一致功能表型的基础。这种独特的构效耦合机制不但为解决领域关键问题“在体区分不同构象CRP的差异性贡献”提供了新策略，而且提示了一种可将“结构约束”和“功能约束”统一起来的“折叠质控阈值”模型，揭示了两者互为表里的内在关联。本项目将系统研究CRP在进化途径中的构效耦合，追溯变构激活的起源和变迁，指导相关动物模型的设计优化；解析折叠决定簇及其作用机制，为“折叠质控阈值”模型提供依据。

How changes in structure, function, and sequence are coupled is the central question of protein evolution. In particular, whether structure or function represents the major constraint shaping protein evolution remains highly controversial. C-reactive protein (CRP) is a prototypical human acute phase reactant with its sequence and structure strongly conserved during the evolution. However, the levels of CRP expression manifest remarkable differences among species, suggesting a unique coupling between structure and function. Our preliminary experiments indicate that CRP may keep a consistent functional phenotype across species with different expression phenotypes by tuning the hidden activities associated with conformational activation. Such a unique coupling between structure and function suggests a folding threshold model that may unify the structural and functional constraints in protein evolution. This project thus aims to further delineate the mechanism underlying the structure-function coupling of CRP and to identify constraints that dictate the folding threshold shaping its evolution.