Structural highlights
Function
HRG_RABIT Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Inhibits rosette formation. Acts as an adapter protein and implicated in regulating many processes such as immune complex and pathogen clearance, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Binds T-cells and alters the cell morphology Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2 (By similarity). Tethers plasminogen to the cell surface.[1]
Publication Abstract from PubMed
Histidine-rich glycoprotein (HRG) is a plasma protein consisting of six distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of two N-terminal domains (N1 and N2), two proline-rich regions (PRR1 and PRR2) which flank a histidine-rich region (HRR), and a C-terminal domain. To date structural information of HRG has largely come from sequence analysis and spectroscopic studies. It is thought that an HRG fragment containing the HRR, released via plasmin-mediated cleavage, acts as a negative regulator of angiogenesis in vivo. However, its release also requires cleavage of a disulphide bond suggesting that its activity is mediated by a redox process. Here, we present a 1.93 A resolution crystal structure of the N2 domain of serum-purified rabbit HRG. The structure confirms that the N2 domain, which along with the N1 domain forms an important molecular interaction site on HRG, possesses a cystatin-like fold composed of a five-stranded anti-parallel beta-sheet wrapped around a five-turn alpha-helix. A native N-linked glycosylation site was identified at Asn184. Moreover, the structure reveals the presence of an S-glutathionyl adduct at Cys185, which has implications for the redox-mediated release of the anti-angiogenic cleavage product from HRG.
Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation.,Kassaar O, McMahon SA, Thompson R, Botting CH, Naismith JH, Stewart AJ Blood. 2014 Feb 5. PMID:24501222[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Juarez JC, Guan X, Shipulina NV, Plunkett ML, Parry GC, Shaw DE, Zhang JC, Rabbani SA, McCrae KR, Mazar AP, Morgan WT, Donate F. Histidine-proline-rich glycoprotein has potent antiangiogenic activity mediated through the histidine-proline-rich domain. Cancer Res. 2002 Sep 15;62(18):5344-50. PMID:12235005
- ↑ Kassaar O, McMahon SA, Thompson R, Botting CH, Naismith JH, Stewart AJ. Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation. Blood. 2014 Feb 5. PMID:24501222 doi:http://dx.doi.org/10.1182/blood-2013-11-535963
