title: Crystal structure of histidine-rich glycoprotein N2 domain reveals redox activity at an interdomain disulfide bridge: implications for angiogenic regulation.
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.
authors: School of Medicine and.
authors: Omar
authors: O
authors: Kassaar
authors: Stephen A
authors: SA
authors: McMahon
authors: Rory
authors: R
authors: Thompson
authors: Catherine H
authors: CH
authors: Botting
authors: James H
authors: JH
authors: Naismith
authors: Alan J
authors: AJ
authors: Stewart
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic; D010084:Oxidation-Reduction; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D000099053:Histidine-Rich Glycoprotein
chemical_list: D004220:Disulfides; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein