title: Flexibility in Mannan-Binding Lectin-Associated Serine Proteases-1 and -2 Provides Insight on Lectin Pathway Activation.
abstract: The lectin pathway of complement is activated by complexes comprising a recognition component (mannose-binding lectin, serum ficolins, collectin-LK or collectin-K1) and a serine protease (MASP-1 or MASP-2). MASP-1 activates MASP-2, and MASP-2 cleaves C4 and C4b-bound C2. To clarify activation, new crystal structures of Ca2+-bound MASP dimers were determined, together with their solution structures from X-ray scattering, analytical ultracentrifugation, and atomistic modeling. Solution structures of the CUB1-EGF-CUB2 dimer of each MASP indicate that the two CUB2 domains were tilted by as much as 90° compared with the crystal structures, indicating considerable flexibility at the EGF-CUB2 junction. Solution structures of the full-length MASP dimers in their zymogen and activated forms revealed similar structures that were much more bent than anticipated from crystal structures. We conclude that MASP-1 and MASP-2 are flexible at multiple sites and that this flexibility may permit both intra- and inter-complex activation.
authors.affiliation: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Ruodan
authors.initials: R
authors.lastname: Nan
authors.affiliation: Departments of Infection, Immunity and Inflammation and Molecular Cell Biology, University of Leicester, University Road, Leicester, LE1 9HN, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Furze
authors.affiliation: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: David W
authors.initials: DW
authors.lastname: Wright
authors.affiliation: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK.
authors.forename: Jayesh
authors.initials: J
authors.lastname: Gor
authors.affiliation: Departments of Infection, Immunity and Inflammation and Molecular Cell Biology, University of Leicester, University Road, Leicester, LE1 9HN, UK.
authors.forename: Russell
authors.initials: R
authors.lastname: Wallis
authors.affiliation: Department of Structural and Molecular Biology, Division of Biosciences, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK. Electronic address: s.perkins@ucl.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Perkins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000737:chemistry* / Q000276:immunology; D002413:Cations, Divalent; D003001:Cloning, Molecular; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics* / Q000276:immunology; D003412:Cricetulus; D018360:Crystallography, X-Ray; D015870:Gene Expression; D006801:Humans; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D002413:Cations, Divalent; D011994:Recombinant Proteins; D050606:Mannose-Binding Protein-Associated Serine Proteases; C570411:Masp1 protein, rat; C491338:Masp2 protein, rat; D002118:Calcium
keywords: X-ray scattering; analytical ultracentrifugation; atomistic modeling; complement; lectin pathway; rat MASP