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Structural and Functional Characterization of a Single-Chain Form of the Recognition Domain of Complement Protein C1q. Moreau Christophe,Bally Isabelle,Chouquet Anne,Bottazzi Barbara,Ghebrehiwet Berhane,Gaboriaud Christine,Thielens Nicole Frontiers in immunology Complement C1q is a soluble pattern recognition molecule comprising six heterotrimeric subunits assembled from three polypeptide chains (A-C). Each heterotrimer forms a collagen-like stem prolonged by a globular recognition domain. These recognition domains sense a wide variety of ligands, including pathogens and altered-self components. Ligand recognition is either direct or mediated by immunoglobulins or pentraxins. Multivalent binding of C1q to its targets triggers immune effector mechanisms mediated via its collagen-like stems. The induced immune response includes activation of the classical complement pathway and enhancement of the phagocytosis of the recognized target. We report here, the first production of a single-chain recombinant form of human C1q globular region (C1q-scGR). The three monomers have been linked in tandem to generate a single continuous polypeptide, based on a strategy previously used for adiponectin, a protein structurally related to C1q. The resulting C1q-scGR protein was produced at high yield in stably transfected 293-F mammalian cells. Recombinant C1q-scGR was correctly folded, as demonstrated by its X-ray crystal structure solved at a resolution of 1.35 Å. Its interaction properties were assessed by surface plasmon resonance analysis using the following physiological C1q ligands: the receptor for C1q globular heads, the long pentraxin PTX3, calreticulin, and heparin. The 3D structure and the binding properties of C1q-scGR were similar to those of the three-chain fragment generated by collagenase digestion of serum-derived C1q. Comparison of the interaction properties of the fragments with those of native C1q provided insights into the avidity component associated with the hexameric assembly of C1q. The interest of this functional recombinant form of the recognition domains of C1q in basic research and its potential biomedical applications are discussed. 10.3389/fimmu.2016.00079
C1q: A fresh look upon an old molecule. Thielens Nicole M,Tedesco Francesco,Bohlson Suzanne S,Gaboriaud Christine,Tenner Andrea J Molecular immunology Originally discovered as part of C1, the initiation component of the classical complement pathway, it is now appreciated that C1q regulates a variety of cellular processes independent of complement activation. C1q is a complex glycoprotein assembled from 18 polypeptide chains, with a C-terminal globular head region that mediates recognition of diverse molecular structures, and an N-terminal collagen-like tail that mediates immune effector mechanisms. C1q mediates a variety of immunoregulatory functions considered important in the prevention of autoimmunity such as the enhancement of phagocytosis, regulation of cytokine production by antigen presenting cells, and subsequent alteration in T-lymphocyte maturation. Furthermore, recent advances indicate additional roles for C1q in diverse physiologic and pathologic processes including pregnancy, tissue repair, and cancer. Finally, C1q is emerging as a critical component of neuronal network refinement and homeostatic regulation within the central nervous system. This review summarizes the classical functions of C1q and reviews novel discoveries within the field. 10.1016/j.molimm.2017.05.025
Complement Component C1q: Historical Perspective of a Functionally Versatile, and Structurally Unusual, Serum Protein. Reid Kenneth B M Frontiers in immunology Complement component C1q plays an important recognition role in adaptive, and innate, immunity through its ability to interact, its six globular head regions, with both immunoglobulin and non-immunoglobulin activators of the complement system, and also in the clearance of cell debris, and by playing a role in regulation of cellular events by interacting with a wide range of cell surface molecules. The presence of collagen-like triple-helical structures within C1q appears crucial to the presentation, and multivalent binding, of the globular heads of C1q to targets, and also to its association with the proenzyme complex of C1r-C1s, to yield the C1 complex. The possible role that movement of these collagen-like structures may play in the activation of the C1 complex is a controversial area, with there still being no definitive answer as to how the first C1r proenzyme molecule becomes activated within the C1 complex, thus allowing it to activate proenzyme C1s, and initiate and the consequent cascade of events in the activation of the classical pathway of complement. The globular heads of C1q are similar to domains found within the tumor necrosis factor (TNF) superfamily of proteins, and have been shown to bind to a very wide range of ligands. In addition to its well-defined roles in infection and immunity, a variety of other functions associated with C1q include possible roles, in the development of problems in the central nervous system, which occur with aging, and perhaps in the regulation of tumor growth. 10.3389/fimmu.2018.00764
Is the A-Chain the Engine That Drives the Diversity of C1q Functions? Revisiting Its Unique Structure. Ghebrehiwet Berhane,Kandov Evelyn,Kishore Uday,Peerschke Ellinor I B Frontiers in immunology The immunopathological functions associated with human C1q are still growing in terms of novelty, diversity, and pathologic relevance. It is, therefore, not surprising that C1q is being recognized as an important molecular bridge between innate and adaptive immunity. The secret of this functional diversity, in turn, resides in the elegant but complex structure of the C1q molecule, which is assembled from three distinct gene products: A, B, and C, each of which has evolved from a separate and unique ancestral gene template. The C1q molecule is made up of 6A, 6B, and 6C polypeptide chains, which are held together through strong covalent and non-covalent bonds to form the 18-chain, bouquet-of-flower-like protein that we know today. The assembled C1q protein displays at least two distinct structural and functional regions: the collagen-like region (cC1q) and the globular head region (gC1q), each being capable of driving a diverse range of ligand- or receptor-mediated biological functions. What is most intriguing, however, is the observation that most of the functions appear to be predominantly driven by the A-chain of the molecule, which begs the question: what are the evolutionary modifications or rearrangements that singularly shaped the primordial A-chain gene to become a pluripotent and versatile component of the intact C1q molecule? Here, we revisit and discuss some of the known unique structural and functional features of the A-chain, which may have contributed to its versatility. 10.3389/fimmu.2018.00162