Histidine‐rich glycoprotein: A novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems

Abstract

Summary Histidine-rich glycoprotein (HRG) is an abundant plasma glycoprotein that has a multidomain structure, interacts with many ligands, and has been shown to regulate a number of important biological processes. HRG ligands include Zn 2+ and haem, tropomyosin, heparin and heparan sulphate, plasminogen, plasmin, fibrinogen, thrombospondin, IgG, Fc γ R and complement. In many cases, the histidine-rich region of the molecule enhances ligand binding following interaction with Zn 2+ or exposure to low pH, conditions associated with sites of tissue injury or tumour growth. The multidomain nature of HRG indicates that it can act as an extracellular adaptor protein, bringing together disparate ligands, particularly on cell surfaces. HRG binds to most cells primarily via heparan sulphate proteoglycans, binding which is also potentiated by elevated free Zn 2+ levels and low pH. Recent reports have shown that HRG can modulate angiogenesis and additional studies have shown that it may regulate other physiological processes such as cell adhesion and migration, fibrinolysis and coagulation, complement activation, immune complex clearance and phagocytosis of apoptotic cells. This review outlines the molecular, structural, biological and clinical properties of HRG as well as describing the role of HRG in various physiological processes.

Histidine-rich Glycoprotein Binds Fibrin(ogen) with High Affinity and Competes with Thrombin for Binding to the γ′-Chain

“…In addition to alterations in the Zn 2ϩ concentration, the activity of HRG can also be modulated by changes in pH, with optimal binding to ligands observed under more acidic conditions. Consequently, the decrease in pH that occurs with reduced tissue perfusion may also enhance the affinity of HRG for both Zn 2ϩ and its ligands (14). Therefore, the current data extend the concept that Zn 2ϩ serves as a dynamic switch that regulates HRG activity and directs it to various pathways involved in hemostasis (14,34).…”

“…In addition to fibrinogen, HRG also binds plasminogen, heparan sulfate, and divalent cations, such as Zn 2ϩ (12,15,16). Therefore, HRG is hypothesized to be an important accessory or adapter protein that brings different ligands together under specific conditions (14).…”

“…Although the plasma concentration of HRG ranges from 1.6 to 2 M, the concentration in platelet-rich thrombi may be higher because HRG is stored in the alpha granules of platelets and is released when platelets are activated (12,13). A 75-kDa glycoprotein, HRG, is composed of two NH 2 -terminal cystatin-like domains, a central histidine-rich region (HRR) flanked by two prolinerich regions, and a COOH-terminal domain (14). In addition to fibrinogen, HRG also binds plasminogen, heparan sulfate, and divalent cations, such as Zn 2ϩ (12,15,16).…”

Activated Platelets Provide a Functional Microenvironment for the Antiangiogenic Fragment of Histidine-Rich Glycoprotein

“…Structurally, HRG consists of three distinct domains: an NH 2 -terminal part with two cystatin (cysteine proteinase inhibitor)-like domains, which classifies HRG as a member of the cystatin superfamily together with, for example, kininogen and fetuin; a central histidine/proline-rich (His/Pro-rich) domain organized in tandem repeats of a consensus GHHPH motif; and a COOH-terminal domain. Multiple binding partners for HRG have been reported, such as heparin/heparan sulfate, divalent cations, and components in the coagulation-fibrinolysis system; plasminogen and fibrinogen; as well as components in the immune system such as T lymphocytes, monocytes/macrophages, and immunoglobulins (19). Monocytes were previously believed to express HRG because HRG binds to the cell surface of monocytes, but more recent data show that RNA is found only in the liver (20).…”

“…HRG is a 75-kDa singlechain heparin-binding plasma protein produced by the liver (19). Structurally, HRG consists of three distinct domains: an NH 2 -terminal part with two cystatin (cysteine proteinase inhibitor)-like domains, which classifies HRG as a member of the cystatin superfamily together with, for example, kininogen and fetuin; a central histidine/proline-rich (His/Pro-rich) domain organized in tandem repeats of a consensus GHHPH motif; and a COOH-terminal domain.…”