Zinc-Dependent Regulation of High-Molecular-Weight Kininogen and the Contact System: Implications for Inflammation, Thrombosis and Vascular Dysfunction

High-molecular-weight kininogen (HMWK) is a multifunctional plasma glycoprotein that serves as both the precursor of bradykinin (BK) and an essential cofactor within the contact activation pathway. Through interactions with factor XII, factor XI, prekallikrein and a range of biological surfaces, HMWK coordinates contact system assembly and links coagulation, inflammation and vascular biology. A growing body of evidence indicates that many of these interactions are strongly regulated by Zn2+, particularly through the histidine-rich D5 domain, which mediates binding to cellular receptors, extracellular matrices and negatively charged activating surfaces. Zn2+ promotes localisation of HMWK and associated contact factors, facilitates contact activation and influences the biological activities of both intact HMWK and cleaved HMWK. Emerging studies also suggest that alterations in extracellular zinc speciation, including those driven by the albumin-fatty acid-zinc switch, may modulate HMWK function and contribute to disease processes associated with inflammation and thrombosis. Beyond its established role in BK generation, HMWK participates in diverse processes including angiogenesis, host defence and responses to pathological surfaces such as amyloid aggregates. Despite significant advances in understanding contact system biology, key questions remain regarding the molecular basis of Zn2+ binding, the structural organisation of HMWK and the mechanisms governing contact activation in vivo. This review summarises current knowledge of HMWK structure and function, with particular emphasis on Zn2+-dependent regulation and the potential importance of zinc speciation in health and disease.