Histidine‐rich glycoprotein is evolutionarily related to the cystatin superfamily

Koide, Takao; Okada, Shoji

doi:10.1016/0014-5793(87)80748-2

Cited by 53 publications

(36 citation statements)

References 23 publications

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“…The structure of HRGP is unique, consisting of a number of discrete domains, including two cystatin-like domains at the NH 2 -terminus, a histidine-rich region, and two proline-rich domains (38).We have identified two regions in HRGP with significant homology to the TSP-1 binding site of CD36. These regions, known as CLESH-1 motifs, are conserved among members of the CD36 gene family and other TSP-1 binding proteins.…”

Section: Discussionmentioning

confidence: 99%

Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1

Simantov¹,

Febbraio²,

Crombie³

et al. 2001

J. Clin. Invest.

101

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Section: Discussionmentioning

confidence: 99%

Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1

Simantov¹,

Febbraio²,

Crombie³

et al. 2001

J. Clin. Invest.

101

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“…Antithrombin III represents one such heparin-binding protein that does not contain a classic heparin-binding motif, where it appears that both linearly contiguous basic heparin-binding residues as well as remote basic residues are appropriately positioned in the structure of the protein to bind heparin (32). The heparinbinding domain of antithrombin III is located within its Nterminal domain, and interestingly, HRG shares ϳ40% sequence identity with this region of antithrombin III (20,21,33 146 in human HRG could possibly constitute heparinbinding residues. However, we can only speculate that these basic amino acids constitute the heparin-binding region within HRG, and clearly, further work is needed to define the specific heparin/heparan sulfate-binding residues within the N1N2 domain of HRG.…”

Section: Discussionmentioning

confidence: 99%

Histidine-rich Glycoprotein Binds to Cell-surface Heparan Sulfate via Its N-terminal Domain following Zn2+ Chelation

Jones

Hulett²,

Parish

2004

Journal of Biological Chemistry

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“…The N1 and N2 domains share a high degree of sequence similarity to members of the cystatin superfamily of cysteine protease inhibitors. 12 Type 1 cystatins (also known as stefins) are characterized by a lack of disulfide bonds, whereas the type 2 cystatins have 2 disulfide bonds. 13 These groups include the proteins cystatin B and cystatin C, respectively, which have proposed roles in the inhibition of tumor neovascularization.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

Kassaar¹,

McMahon

Thompson³

et al. 2014

Blood

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Key Points• The x-ray crystal structure of the N2 domain from HRG at 1.93Å resolution is presented.• The structure reveals an S-glutathionyl adduct at Cys185, which has implications for angiogenic regulation.Histidine-rich glycoprotein (HRG) is a plasma protein consisting of 6 distinct functional domains and is an important regulator of key cardiovascular processes, including angiogenesis and coagulation. The protein is composed of 2 N-terminal domains (N1 and N2), 2 proline-rich regions (PRR1 and PRR2) that 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 1.93Å 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 5-stranded antiparallel b-sheet wrapped around a 5-turn a-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 antiangiogenic cleavage product from HRG. (Blood. 2014;123(12):1948-1955 Introduction Histidine-rich glycoprotein (HRG) is a plasma protein that regulates angiogenesis, coagulation, and immune function in vertebrates. Human HRG has an approximate mass of 70 kDa and is present in plasma at low micromolar concentrations (ca ;1.5 mM). The protein is arranged into 6 domains: 2 N-terminal domains (N1 and N2), a central histidine-rich region (HRR) flanked by 2 proline rich regions (PRR1 and PRR2), and a C-terminal domain (C). The N1, N2, and C domains are highly conserved between species, as is an arrangement of 6 disulfide bridges (Figure 1). In plasma, HRG binds to and regulates the function of a diverse variety of targets that include fibrinogen, plasminogen, thrombospondin, immunoglobulin G (IgG), complement factors, and heparin as well as cell-surface molecules such as Fcg receptors and heparan sulfate.1-9 HRG binds divalent metal cations within the HRR. 10 In particular, Zn 21 is known to bind this region and can modulate HRG activity by altering the protein's affinity for other targets. 11HRG is heavily glycosylated; the human protein has 6 putative N-linked glycosylation sites.11 The histidine-and proline-rich regions are predicted to be intrinsically disordered but N1, N2, and the C-terminal domains are likely to have ordered structures. The N1 and N2 domains share a high degree of sequence similarity to members of the cystatin superfamily of cysteine protease inhibitors.12 Type 1 cystatins (also known as stefins) are characterized b...

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Histidine‐rich glycoprotein is evolutionarily related to the cystatin superfamily

Cited by 53 publications

References 23 publications

Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1

Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1

Histidine-rich Glycoprotein Binds to Cell-surface Heparan Sulfate via Its N-terminal Domain following Zn2+ Chelation

Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation

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