Reactome | factor XIIa binds HRG

factor XIIa binds HRG

Stable Identifier

R-HSA-9653879

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region

ReviewStatus

5/5

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Histidine-rich glycoprotein (HRG) is produced in the liver and circulates in plasma at a concentration of ~1–3 μM. HRG has been also detected in the platelet α-granules, which are released upon platelet activation (Leung LL et al., 1983). In the circulation, HRG binds factor XIIa (FXIIa) with high affinity, but does not interact with zymogen FXII, FXI, or FXIa (MacQuarrie JL et al., 2011; Truong TK et al., 2022). The interaction between HRG and FXIIa is mediated by the histidine-rich region (HRR) of HRG (Truong TK et al., 2022) and is enhanced in the presence of Zn²(+) (MacQuarrie JL et al., 2011). HRG binding to factor XIIa inhibits factor XIIa-mediated activation of factor XII, factor XI and prekallikrein (MacQuarrie JL et al. 2011; Truong TK et al., 2022). HRG also neutralizes polyanionic surfaces, that trigger activation of FXII in human and mouse plasma (Malik RA et al., 2021; Truong TK et al., 2022). Furthermore, studies with human and rabbit plasma showed that HRG attenuates catheter-induced FXII autoactivation and thrombin generation suggesting that HRG (or HRG analogs) may serve as a protective factor to reduce catheter-related thrombotic complications in patients (Malik RA et al., 2023; reviewed by Schmaier AH 2023). Finally, upon reduction by protein disulfide isomerase (PDI), HRG exhibits enhanced procoagulant and anticoagulant activities through neutralization of endothelial heparan sulfate (HS) and increased inhibition of factor XIIa (FXIIa), respectively (Lv K et al., 2024).

Literature References

PubMed ID	Title	Journal	Year
34967109	Identification of the histidine-rich glycoprotein domains responsible for contact pathway inhibition Truong, TK, Malik, RA, Yao, X, Fredenburgh, JC, Stafford, AR, Madarati, HM, Kretz, CA, Weitz, JI	J Thromb Haemost	2022
21304106	Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation MacQuarrie, JL, Stafford, AR, Yau, JW, Leslie, BA, Vu, TT, Fredenburgh, JC, Weitz, JI	Blood	2011