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      Structure of the C1r–C1s interaction of the C1 complex of complement activation

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          Significance

          C1 is a large complex that triggers the destruction of invading pathogens via lysis or by stimulation of innate and adaptive immune processes. It is composed of C1q, a protein with a bouquet-like architecture, together with a tetramer assembled from two copies each of the serine proteases C1r and C1s, which activate when C1q binds to a pathogen surface. Here we describe detailed structures that show how C1r and C1s interact via an extensive interface encompassing the N-terminal regions of both proteases. Our findings reveal how the protease tetramer is organized and suggest a mechanism for the assembly and activation of C1.

          Abstract

          The multiprotein complex C1 initiates the classical pathway of complement activation on binding to antibody–antigen complexes, pathogen surfaces, apoptotic cells, and polyanionic structures. It is formed from the recognition subcomponent C1q and a tetramer of proteases C1r 2C1s 2 as a Ca 2+-dependent complex. Here we have determined the structure of a complex between the CUB1-EGF-CUB2 fragments of C1r and C1s to reveal the C1r–C1s interaction that forms the core of C1. Both fragments are L-shaped and interlock to form a compact antiparallel heterodimer with a Ca 2+ from each subcomponent at the interface. Contacts, involving all three domains of each protease, are more extensive than those of C1r or C1s homodimers, explaining why heterocomplexes form preferentially. The available structural and biophysical data support a model of C1r 2C1s 2 in which two C1r-C1s dimers are linked via the catalytic domains of C1r. They are incompatible with a recent model in which the N-terminal domains of C1r and C1s form a fixed tetramer. On binding to C1q, the proteases become more compact, with the C1r-C1s dimers at the center and the six collagenous stems of C1q arranged around the perimeter. Activation is likely driven by separation of the C1r-C1s dimer pairs when C1q binds to a surface. Considerable flexibility in C1s likely facilitates C1 complex formation, activation of C1s by C1r, and binding and activation of downstream substrates C4 and C4b-bound C2 to initiate the reaction cascade.

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          Most cited references28

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          Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

          The structure of a protein triple helix has been determined at 1.9 angstrom resolution by x-ray crystallographic studies of a collagen-like peptide containing a single substitution of the consensus sequence. This peptide adopts a triple-helical structure that confirms the basic features determined from fiber diffraction studies on collagen: supercoiling of polyproline II helices and interchain hydrogen bonding that follows the model II of Rich and Crick. In addition, the structure provides new information concerning the nature of this protein fold. Each triple helix is surrounded by a cylinder of hydration, with an extensive hydrogen bonding network between water molecules and peptide acceptor groups. Hydroxyproline residues have a critical role in this water network. The interaxial spacing of triple helices in the crystal is similar to that in collagen fibrils, and the water networks linking adjacent triple helices in the crystal structure are likely to be present in connective tissues. The breaking of the repeating (X-Y-Gly)n pattern by a Gly-->Ala substitution results in a subtle alteration of the conformation, with a local untwisting of the triple helix. At the substitution site, direct interchain hydrogen bonds are replaced with interstitial water bridges between the peptide groups. Similar conformational changes may occur in Gly-->X mutated collagens responsible for the diseases osteogenesis imperfecta, chondrodysplasias, and Ehlers-Danlos syndrome IV.
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            The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties.

            C1q is a versatile recognition protein that binds to an amazing variety of immune and non-immune ligands and triggers activation of the classical pathway of complement. The crystal structure of the C1q globular domain responsible for its recognition properties has now been solved and refined to 1.9 A of resolution. The structure reveals a compact, almost spherical heterotrimeric assembly held together mainly by non-polar interactions, with a Ca2+ ion bound at the top. The heterotrimeric assembly of the C1q globular domain appears to be a key factor of the versatile recognition properties of this protein. Plausible three-dimensional models of the C1q globular domain in complex with two of its physiological ligands, C-reactive protein and IgG, are proposed, highlighting two of the possible recognition modes of C1q. The C1q/human IgG1 model suggests a critical role for the hinge region of IgG and for the relative orientation of its Fab domain in C1q binding.
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              Paths reunited: Initiation of the classical and lectin pathways of complement activation.

              Understanding the structural organisation and mode of action of the initiating complex of the classical pathway of complement activation (C1) has been a central goal in complement biology since its isolation almost 50 years ago. Nevertheless, knowledge is still incomplete, especially with regard to the interactions between its subcomponents C1q, C1r and C1s that trigger activation upon binding to a microbial target. Recent studies have provided new insights into these interactions, and have revealed unexpected parallels with initiating complexes of the lectin pathway of complement: MBL-MASP and ficolin-MASP. Here, we develop and expand these concepts and delineate their implications towards the key aspects of complement activation via the classical and lectin pathways.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                23 January 2018
                8 January 2018
                8 January 2018
                : 115
                : 4
                : 768-773
                Affiliations
                [1] aDepartment of Infection, Immunity, and Inflammation, University of Leicester , Leicester LE1 9HN, United Kingdom;
                [2] bLeicester Institute of Structural and Chemical Biology, University of Leicester , Leicester LE1 7RH, United Kingdom;
                [3] cSchool of Allied Health Sciences, De Montfort University , Leicester LE1 9BH, United Kingdom;
                [4] dClinical Sciences Research Laboratories, Warwick Medical School and University Hospital Coventry & Warwickshire NHS Trust , Coventry CV2 2DX, United Kingdom;
                [5] eDepartment of Molecular and Cell Biology, University of Leicester , Leicester LE1 9HN, United Kingdom
                Author notes
                1To whom correspondence should be addressed. Email: rw73@ 123456le.ac.uk .

                Edited by Douglas T. Fearon, Cornell University, Cambridge, United Kingdom, and approved December 8, 2017 (received for review October 26, 2017)

                Author contributions: W.J.S., D.A.M., and R.W. designed research; J.O.M.A., U.V.G., C.M.F., X.S.-G., F.B., J.E.M., and R.W. performed research; X.S.-G., P.C.E.M., and R.W. analyzed data; U.V.G., D.A.M., and R.W. wrote the paper; and U.V.G., X.S.-G., W.J.S., and P.C.E.M. edited the paper.

                Author information
                http://orcid.org/0000-0001-8927-0864
                http://orcid.org/0000-0003-1762-9238
                Article
                201718709
                10.1073/pnas.1718709115
                5789954
                29311313
                be3f1a1d-507f-4e4f-97b8-54f77792cc8e
                Copyright © 2018 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 6
                Funding
                Funded by: RCUK | Medical Research Council (MRC) 501100000265
                Award ID: G1000191/1
                Categories
                Biological Sciences
                Immunology and Inflammation

                complement,structural biology,classical pathway,x-ray crystallography

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