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

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Author(s)

Omar Kassaar, Stephen A McMahon, Rory Thompson, Catherine H Botting, James H Naismith, Alan J. Stewart

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Abstract

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 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 five-stranded anti-parallel β-sheet wrapped around a five-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 anti-angiogenic cleavage product from HRG.
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Original languageEnglish
Pages (from-to)1948-1955
Number of pages8
JournalBlood
Volume123
Issue number12
Early online date5 Feb 2014
DOIs
Publication statusPublished - 20 Mar 2014

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