Calcium-dependent conformational transitions and ligand binding regulation of C-reactive protein: a comprehensive review.

Abstract

C-reactive protein (CRP) is a crucial biomarker of inflammation and a primary pattern recognition molecule of the innate immune system. It is predominantly synthesized by hepatocytes and subsequently released into the circulation. The concentration of CRP in plasma can increase significantly, sometimes by up to a thousand-fold, in the presence of infection, inflammation, or tissue damage, making it a widely used clinical indicator of inflammatory status. The distinctive structure of pentameric CRP (pCRP), coupled with the specific functions of its recognition face (B-face) and effector face (A-face) as well as its calcium-dependent ligand recognition, dictates its structural and functional characteristics. This review presents a thorough analysis of the structure and functional surfaces of CRP, focusing on the dual regulatory role of calcium ions (Ca²⁺) in maintaining structural stability and facilitating ligand recognition. It further examines the historical and mechanistic basis of CRP conformational conversion, emphasizing the distinction between Ca²⁺ depletion-induced destabilization and physiologically relevant membrane-associated remodeling that can occur in the continued presence of Ca²⁺. The present review explores the interaction mechanisms of CRP with its ligands, as well as the influence of the microenvironment on CRP's conformational dynamics and functional diversity. This review could provide new prospects for designing targeted drugs according to the structural characteristics of CRP.