MOE Key Laboratory of Environment and Genes Related to Diseases, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China.
MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China.
Front Immunol. 2020 Mar 31;11:583. doi: 10.3389/fimmu.2020.00583. eCollection 2020.
C-reactive protein (CRP) is an acute phase reactant secreted by hepatocytes as a pentamer. The structure formation of pentameric CRP has been demonstrated to proceed in a stepwise manner in live cells. Here, we further dissect the sequence determinants that underlie the key steps in cellular folding and assembly of CRP. The initial folding of CRP subunits depends on a leading sequence with a conserved dipeptide that licenses the formation of the hydrophobic core. This drives the bonding of the intra-subunit disulfide requiring a favorable niche largely conferred by a single residue within the C-terminal helix. A conserved salt bridge then mediates the assembly of folded subunits into pentamer. The pentameric assembly harbors a pronounced plasticity in inter-subunit interactions, which may form the basis for a reversible activation of CRP in inflammation. These results provide insights into how sequence constraints are evolved to dictate structure and function of CRP.
C-反应蛋白（CRP）是一种急性时相反应蛋白，由肝细胞以五聚体的形式分泌。已经证明，五聚体 CRP 的结构形成在活细胞中是逐步进行的。在这里，我们进一步剖析了细胞内折叠和 CRP 组装的关键步骤所依赖的序列决定因素。CRP 亚基的初始折叠取决于一个保守二肽的前导序列，该序列允许形成疏水性核心。这促使形成需要合适的局部环境的亚单位间二硫键，而该局部环境主要由 C 端螺旋内的单个残基赋予。然后，一个保守的盐桥介导折叠亚基组装成五聚体。五聚体组装具有明显的亚基间相互作用的可塑性，这可能是 CRP 在炎症中可逆激活的基础。这些结果提供了关于序列约束如何进化以决定 CRP 的结构和功能的见解。
