title: Solution Structures of Complement C2 and Its C4 Complexes Propose Pathway-specific Mechanisms for Control and Activation of the Complement Proconvertases.
abstract: The lectin (LP) and classical (CP) pathways are two of the three main activation cascades of the complement system. These pathways start with recognition of different pathogen- or danger-associated molecular patterns and include identical steps of proteolytic activation of complement component C4, formation of the C3 proconvertase C4b2, followed by cleavage of complement component C2 within C4b2 resulting in the C3 convertase C4b2a. Here, we describe the solution structures of the two central complexes of the pathways, C3 proconvertase and C3 convertase, as well as the unbound zymogen C2 obtained by small angle x-ray scattering analysis. We analyzed both native and enzymatically deglycosylated C4b2 and C2 and showed that the resulting structural models were independent of the glycans. The small angle x-ray scattering-derived models suggest a different activation mode for the CP/LP C3 proconvertase as compared with that established for the alternative pathway proconvertase C3bB. This is likely due to the rather different structural and functional properties of the proteases activating the proconvertases. The solution structure of a stabilized form of the active CP/LP C3 convertase C4b2a is strikingly similar to the crystal structure of the alternative pathway C3 convertase C3bBb, which is in accordance with their identical functions in cleaving the complement proteins C3 and C5.
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-800 Aarhus, Denmark.
authors.forename: Sofia
authors.initials: S
authors.lastname: Mortensen
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-800 Aarhus, Denmark.
authors.forename: Jan K
authors.identifier: 0000-0002-7131-1418
authors.initials: JK
authors.lastname: Jensen
authors.affiliation: From the Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10C, DK-800 Aarhus, Denmark gra@mbg.au.dk.
authors.forename: Gregers R
authors.identifier: 0000-0001-6292-3319
authors.initials: GR
authors.lastname: Andersen
mesh_terms: D003175:Complement C2 / Q000737:chemistry*; D050577:Complement C3-C5 Convertases / Q000737:chemistry*; D003181:Complement C4 / Q000737:chemistry*; D006801:Humans; D014961:X-Ray Diffraction
chemical_list: D003175:Complement C2; D003181:Complement C4; D050577:Complement C3-C5 Convertases
keywords: complement system; convertase; innate immunity; protease; small angle x-ray scattering (SAXS); structural biology