title: Ceruloplasmin: macromolecular assemblies with iron-containing acute phase proteins.
abstract: Copper-containing ferroxidase ceruloplasmin (Cp) forms binary and ternary complexes with cationic proteins lactoferrin (Lf) and myeloperoxidase (Mpo) during inflammation. We present an X-ray crystal structure of a 2Cp-Mpo complex at 4.7 Å resolution. This structure allows one to identify major protein-protein interaction areas and provides an explanation for a competitive inhibition of Mpo by Cp and for the activation of p-phenylenediamine oxidation by Mpo. Small angle X-ray scattering was employed to construct low-resolution models of the Cp-Lf complex and, for the first time, of the ternary 2Cp-2Lf-Mpo complex in solution. The SAXS-based model of Cp-Lf supports the predicted 1:1 stoichiometry of the complex and demonstrates that both lobes of Lf contact domains 1 and 6 of Cp. The 2Cp-2Lf-Mpo SAXS model reveals the absence of interaction between Mpo and Lf in the ternary complex, so Cp can serve as a mediator of protein interactions in complex architecture. Mpo protects antioxidant properties of Cp by isolating its sensitive loop from proteases. The latter is important for incorporation of Fe(3+) into Lf, which activates ferroxidase activity of Cp and precludes oxidation of Cp substrates. Our models provide the structural basis for possible regulatory role of these complexes in preventing iron-induced oxidative damage.
authors.affiliation: Institute of Crystallography RAS, Moscow, Russia. vsamygina@cicbiogune.es
authors.forename: Valeriya R
authors.initials: VR
authors.lastname: Samygina
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Sokolov
authors.forename: Gleb
authors.initials: G
authors.lastname: Bourenkov
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Petoukhov
authors.forename: Maria O
authors.initials: MO
authors.lastname: Pulina
authors.forename: Elena T
authors.initials: ET
authors.lastname: Zakharova
authors.forename: Vadim B
authors.initials: VB
authors.lastname: Vasilyev
authors.forename: Hans
authors.initials: H
authors.lastname: Bartunik
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
mesh_terms: D000209:Acute-Phase Proteins / Q000737:chemistry / Q000378:metabolism; D002570:Ceruloplasmin / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D007781:Lactoferrin / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009195:Peroxidase / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D012996:Solutions
chemical_list: D000209:Acute-Phase Proteins; D046912:Multiprotein Complexes; D012996:Solutions; D007501:Iron; D009195:Peroxidase; D002570:Ceruloplasmin; D007781:Lactoferrin