title: Structure and activation of C1, the complex initiating the classical pathway of the complement cascade.
abstract: The complement system is an important antimicrobial and inflammation-generating component of the innate immune system. The classical pathway of complement is activated upon binding of the 774-kDa C1 complex, consisting of the recognition molecule C1q and the tetrameric protease complex C1r2s2, to a variety of activators presenting specific molecular patterns such as IgG- and IgM-containing immune complexes. A canonical model entails a C1r2s2with its serine protease domains tightly packed together in the center of C1 and an intricate intramolecular reaction mechanism for activation of C1r and C1s, induced upon C1 binding to the activator. Here, we show that the serine protease domains of C1r and C1s are located at the periphery of the C1r2s2tetramer both when alone or within the nonactivated C1 complex. Our structural studies indicate that the C1 complex adopts a conformation incompatible with intramolecular activation of C1, suggesting instead that intermolecular proteolytic activation between neighboring C1 complexes bound to a complement activating surface occurs. Our results rationalize how a multitude of structurally unrelated molecular patterns can activate C1 and suggests a conserved mechanism for complement activation through the classical and the related lectin pathway.
authors.affiliation: Department of Biomedicine, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mortensen
authors.affiliation: Center for Stochastic Geometry and Advanced Bioimaging, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Sander
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Rasmus K
authors.initials: RK
authors.lastname: Jensen
authors.affiliation: Interdisciplinary Nanoscience Center, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Jan Skov
authors.initials: JS
authors.lastname: Pedersen
authors.affiliation: Department of Biomedicine, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Golas
authors.affiliation: Department of Biomedicine, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Jensenius
authors.affiliation: Department of Biomedicine, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Annette G
authors.initials: AG
authors.lastname: Hansen
authors.affiliation: Department of Biomedicine, Aarhus University, DK8000 Aarhus, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.affiliation: Department of Molecular Biology and Genetics, Aarhus University, DK8000 Aarhus, Denmark; gra@mbg.au.dk.
authors.forename: Gregers R
authors.identifier: 0000-0001-6292-3319
authors.initials: GR
authors.lastname: Andersen
mesh_terms: D015923:Complement C1r / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003173:Complement C1s / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000502:physiology*; D004789:Enzyme Activation; D005813:Genes, Synthetic; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D008854:Microscopy, Electron; D008958:Models, Molecular; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D053838:Scattering, Small Angle; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D011994:Recombinant Proteins; D015923:Complement C1r; D003173:Complement C1s
keywords: complement; innate immunity; proteolytic cascade; structural biology