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

DOI: 10.1182/blood-2013-11-535963 DOI Help
PMID: 24501222 PMID Help

Authors: O. Kassaar (University of St. Andrews) , S. A. Mcmahon (University of St. Andrews) , R. Thompson (University of St. Andrews) , C. H. Botting (University of St. Andrews) , J. H. Naismith (University of St. Andrews) , A. J. Stewart (University of St. Andrews)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Blood , VOL 123 (12) , PAGES 1948 - 1955

State: Published (Approved)
Published: March 2014

Abstract: 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 1.93 Å 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 β-sheet wrapped around a 5-turn α-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.. - See more at:

Journal Keywords: Animals ; Crystallography ; X-Ray ; Disulfides ; Humans ; Models ; Molecular ; Neovascularization ; Physiologic ; Oxidation-Reduction ; Protein; Secondary ; Protein; Tertiary ; Proteins ; Rabbits ; Sequence; Amino Acid

Subject Areas: Biology and Bio-materials

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

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