Determination of the disulphide bridge arrangement of bovine histidine‐rich glycoprotein

Sørensen, Charlotte Brandt; Krogh-Pedersen, Helene; Petersen, Torben E.

doi:10.1016/0014-5793(93)80945-q

Cited by 23 publications

(24 citation statements)

References 31 publications

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“…Based on the experimental detection of the disulfide bridges, it has been determined that the 12 cysteine residues of bovine HPRG form 6 disulfide bonds [31]. Genome sequence data indicate that also rabbit HPRG contains 12 cysteine residues.…”

Section: Disulfide Bridges Arrangement In Hprgmentioning

confidence: 99%

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Ronca

Raggi

2015

Biochimie

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Section: Disulfide Bridges Arrangement In Hprgmentioning

confidence: 99%

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Ronca

Raggi

2015

Biochimie

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“…The other interdomain disulfide is unique to HRG and connects the N2 domain to a linker region between the HRR and PRR2 domains (Figure 1). 28 A peptide corresponding to the HRR/ PRR fragment has been identified in human tissue samples but the mechanism by which the interdomain disulfide is reduced is not known. 29 Using x-ray crystallography we present the first structural characterization of HRG.…”

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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“…Although HRG has been classified as a member of the cystatin supergene-family that are generally known as cysteine protease inhibitors, 9 no protease inhibitory activity has been reported for HRG. HRG also contains 4 intradomain and 2 interdomain disulfide bridges, 10 and 6 predicted N-linked glycosylation sites. 2,5 The protein and gene structure of HRG have been reviewed in detail by Jones et al 3 A variety of molecules have been shown to interact with HRG, including heme, 11 Zn 2ϩ , 12 plasminogen, 13 heparanase, 14 fibrinogen, 15 thrombospondin (TSP), 16 vasculostatin, 17 immunoglobulin G (IgG), 18 complement components, 18,19 and heparin.…”

Section: Introductionmentioning

confidence: 99%

Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma

Poon

Patel

Davis

et al. 2011

Blood

201

209

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Histidine-rich glycoprotein (HRG), also known as histidine-proline-rich glyco-protein, is an abundant and well-characterized protein of vertebrate plasma. HRG has a multidomain structure that allows the molecule to interact with many ligands, including heparin, phospholipids, plasminogen, fibrinogen, immunoglobulin G, C1q, heme, and Zn²(+). The ability of HRG to interact with various ligands simultaneously has suggested that HRG can function as an adaptor molecule and regulate numerous important biologic processes, such as immune complex/necrotic cell/pathogen clearance, cell adhesion, angiogenesis, coagulation, and fibrinolysis. The present review covers the proposed multifunctional roles of HRG with a focus on recent findings that have led to its emergence as a key regulator of immunity and vascular biology. Also included is a discussion of the striking functional similarities between HRG and other important multifunctional proteins found in plasma, such as C-reactive protein, C1q, β₂ glycoprotein I, and thrombospondin-1.

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Determination of the disulphide bridge arrangement of bovine histidine‐rich glycoprotein

Cited by 23 publications

References 31 publications

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

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

Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma

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