4CCV

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

Summary for 4CCV

• Entry DOI: 10.2210/pdb4ccv/pdb
• Descriptor: HISTIDINE-RICH GLYCOPROTEIN, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, GLUTATHIONE, ... (5 entities in total)
• Functional Keywords: blood clotting, coagulation, cystatin, s-glutathionylation
• Biological source: ORYCTOLAGUS CUNICULUS (RABBIT)
• Total number of polymer chains: 1
• Total formula weight: 14513.82

Authors

McMahon, S.A.,Kassaar, O.,Stewart, A.J.,Naismith, J.H. (deposition date: 2013-10-29, release date: 2014-02-19, Last modification date: 2020-07-29)

Primary citation

Kassaar, O.,Mcmahon, S.A.,Thompson, R.,Botting, C.H.,Naismith, J.H.,Stewart, A.J.
Crystal Structure of Histidine-Rich Glycoprotein N2 Domain Reveals Redox Activity at an Interdomain Disulfide Bridge: Implications for Angiogenic Regulation.
Blood, 123:1948-, 2014

PubMed 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.

PubMed: 24501222
DOI: 10.1182/BLOOD-2013-11-535963

Experimental method

X-RAY DIFFRACTION (1.93 Å)