title: Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes.
abstract: Defining mechanisms governing translation of molecular binding events into immune activation is central to understanding immune function. In the lectin pathway of complement, the pattern recognition molecules (PRMs) mannan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase. MASP-1 was recently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predominant oligomeric forms of MBL carry only a single MASP homodimer. This prompted us to investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition on ligand surfaces. We demonstrate that intercomplex activation occurs between discrete PRM/MASP complexes. PRM ligand binding does not directly escort the transition of MASP from zymogen to active enzyme in the PRM/MASP complex; rather, clustering of PRM/MASP complexes directly causes activation. Our results support a clustering-based mechanism of activation, fundamentally different from the conformational model suggested for the classical pathway of complement.
authors.affiliation: Department of Biomedicine, Health, Aarhus University, 8000 Aarhus C, Denmark; sdegn@biomed.au.dk.
authors.forename: Søren E
authors.initials: SE
authors.lastname: Degn
authors.affiliation: Department of Biomedicine, Health, Aarhus University, 8000 Aarhus C, Denmark;
authors.forename: Troels R
authors.initials: TR
authors.lastname: Kjaer
authors.affiliation: Department of Molecular Biology and Genetics, Science and Technology, Aarhus University, 8000 Aarhus C, Denmark; and.
authors.forename: Rune T
authors.initials: RT
authors.lastname: Kidmose
authors.affiliation: Department of Biomedicine, Health, Aarhus University, 8000 Aarhus C, Denmark;
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Jensen
authors.affiliation: Department of Biomedicine, Health, Aarhus University, 8000 Aarhus C, Denmark;
authors.forename: Annette G
authors.initials: AG
authors.lastname: Hansen
authors.affiliation: Dr. John T. Macdonald Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.affiliation: Department of Biomedicine, Health, Aarhus University, 8000 Aarhus C, Denmark;
authors.forename: Jens C
authors.initials: JC
authors.lastname: Jensenius
authors.affiliation: Department of Molecular Biology and Genetics, Science and Technology, Aarhus University, 8000 Aarhus C, Denmark; and.
authors.forename: Gregers R
authors.initials: GR
authors.lastname: Andersen
authors.affiliation: Department of Biomedicine, Health, Aarhus University, 8000 Aarhus C, Denmark;
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
mesh_terms: D003167:Complement Activation; D006801:Humans; D037102:Lectins / Q000378:metabolism; D008024:Ligands; D008351:Mannans / Q000378:metabolism; D037601:Mannose-Binding Lectin / Q000378:metabolism; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000378:metabolism; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D051192:Receptors, Pattern Recognition / Q000378:metabolism*; D000097604:Ficolins
chemical_list: D037102:Lectins; D008024:Ligands; D008351:Mannans; D037601:Mannose-Binding Lectin; D050606:Mannose-Binding Protein-Associated Serine Proteases; D046912:Multiprotein Complexes; D051192:Receptors, Pattern Recognition; D000097604:Ficolins
keywords: collectin; homeostasis; inflammation; innate immunity