title: Structural insights into the initiating complex of the lectin pathway of complement activation.
abstract: The proteolytic cascade of the complement system is initiated when pattern-recognition molecules (PRMs) bind to ligands, resulting in the activation of associated proteases. In the lectin pathway of complement, the complex of mannan-binding lectin (MBL) and MBL-associated serine protease-1 (MASP-1) initiates the pathway by activating a second protease, MASP-2. Here we present a structural study of a PRM/MASP complex and derive the overall architecture of the 450 kDa MBL/MASP-1 complex using small-angle X-ray scattering and electron microscopy. The serine protease (SP) domains from the zymogen MASP-1 dimer protrude from the cone-like MBL tetramer and are separated by at least 20 nm. This suggests that intracomplex activation within a single MASP-1 dimer is unlikely and instead supports intercomplex activation, whereby the MASP SP domains are accessible to nearby PRM-bound MASPs. This activation mechanism differs fundamentally from the intracomplex initiation models previously proposed for both the lectin and the classical pathway.
authors.affiliation: Department of Biomedicine, Aarhus University, Bartholins Allé 6 and Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
authors.forename: Troels R
authors.initials: TR
authors.lastname: Kjaer
authors.affiliation: Department of Clinical Medicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
authors.forename: Le T M
authors.initials: le TM
authors.lastname: Le
authors.affiliation: Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus, Denmark; Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus, Denmark.
authors.forename: Jan Skov
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Department of Clinical Medicine, Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark; Center for Stochastic Geometry and Advanced Bioimaging (CSGB), Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Sander
authors.affiliation: Department of Biomedicine, Aarhus University, Bartholins Allé 6 and Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark; Center for Stochastic Geometry and Advanced Bioimaging (CSGB), Aarhus University, Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Golas
authors.affiliation: Department of Biomedicine, Aarhus University, Bartholins Allé 6 and Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark.
authors.forename: Jens Christian
authors.initials: JC
authors.lastname: Jensenius
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10, 8000 Aarhus, Denmark.
authors.forename: Gregers R
authors.initials: GR
authors.lastname: Andersen
authors.affiliation: Department of Biomedicine, Aarhus University, Bartholins Allé 6 and Wilhelm Meyers Allé 3, 8000 Aarhus, Denmark. Electronic address: st@biomed.au.dk.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
mesh_terms: D002850:Chromatography, Gel; D003167:Complement Activation / Q000235:genetics / Q000502:physiology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics* / Q000502:physiology; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000737:chemistry* / Q000378:metabolism; D008854:Microscopy, Electron; D008958:Models, Molecular; D011487:Protein Conformation; D051192:Receptors, Pattern Recognition / Q000737:chemistry* / Q000378:metabolism; D053838:Scattering, Small Angle
chemical_list: D051192:Receptors, Pattern Recognition; C084067:MASP1 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases