The Human C1q Globular Domain: Structure and Recognition of Non-Immune Self Ligands
ABSTRACT C1q, the ligand-binding unit of the C1 complex of complement, is a pattern recognition molecule with the unique ability to sense an amazing variety of targets, including a number of altered structures from self, such as apoptotic cells. The three-dimensional structure of its C-terminal globular domain, responsible for its recognition function, has been solved by X-ray crystallography, revealing a tightly packed heterotrimeric assembly with marked differences in the surface patterns of the subunits, and yielding insights into its versatile binding properties. In conjunction with other approaches, this same technique has been used recently to decipher the mechanisms that allow this domain to interact with various non-immune self ligands, including molecules known to provide eat-me signals on apoptotic cells, such as phosphatidylserine and DNA. These investigations provide evidence for a common binding area for these ligands located in subunit C of the C1q globular domain, and suggest that ligand recognition through this area down-regulates C1 activation, hence contributing to the control of the inflammatory reaction. The purpose of this article is to give an overview of these advances which represent a first step toward understanding the recognition mechanisms of C1q and their biological implications.
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ABSTRACT: The Fc region of IgG antibodies, important for effector functions such as antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement activation, contains an oligosaccharide moiety covalently attached to each CH2 domain. The oligosaccharide not only orients the CH2 domains but plays an important role in influencing IgG effector function, and engineering the IgG-Fc oligosaccharide moiety is an important aspect in the design of therapeutic monoclonal IgG antibodies. Recently we reported the crystal structure of glycosylated IgG4-Fc, revealing structural features that could explain the anti-inflammatory biological properties of IgG4 compared with IgG1. We now report the crystal structure of enzymatically deglycosylated IgG4-Fc, derived from human serum, at 2.7Å resolution. Intermolecular CH2-CH2 domain interactions partially bury the CH2 domain surface that would otherwise be exposed by the absence of oligosaccharide, and two Fc molecules are interlocked in a symmetric, open conformation. The conformation of the CH2 domain DE loop, to which oligosaccharide is attached, is altered in the absence of carbohydrate. Furthermore, the CH2 domain FG loop, important for Fcγ receptor and C1q binding, adopts two different conformations. One loop conformation is unique to IgG4 and would disrupt binding, consistent with IgG4's anti-inflammatory properties. The second is similar to the conserved conformation found in IgG1, suggesting that in contrast to IgG1, the IgG4 CH2 FG loop is dynamic. Finally, crystal packing reveals a hexameric arrangement of IgG4-Fc molecules, providing further clues about the interaction between C1q and IgG.Molecular Immunology 06/2014; 62(1):46-53. DOI:10.1016/j.molimm.2014.05.015 · 3.00 Impact Factor
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ABSTRACT: Conglutinin, a collagenous C-type lectin, acts as soluble pattern recognition receptor (PRR) in recognition of pathogens. In the present study, genes encoding neck and carbohydrate recognition domain (NCRD) of conglutinin in goat and blackbuck were amplified, cloned, and sequenced. The obtained 488 bp ORFs encoding NCRD were submitted to NCBI with accession numbers KC505182 and KC505183. Both nucleotide and predicted amino acid sequences were analysed with sequences of other ruminants retrieved from NCBI GenBank using DNAstar and Megalign5.2 software. Sequence analysis revealed maximum similarity of blackbuck sequence with wild ruminants like nilgai and buffalo, whereas goat sequence displayed maximum similarity with sheep sequence at both nucleotide and amino acid level. Phylogenetic analysis further indicated clear divergence of wild ruminants from the domestic ruminants in separate clusters. The predicted secondary structures of NCRD protein in goat and blackbuck using SWISSMODEL ProtParam online software were found to possess 6 beta-sheets and 3 alpha-helices which are identical to the result obtained in case of sheep, cattle, buffalo, and nilgai. However, quaternary structure in goat, sheep, and cattle was found to differ from that of buffalo, nilgai, and blackbuck, suggesting a probable variation in the efficiency of antimicrobial activity among wild and domestic ruminants.BioMed Research International 06/2014; 2014:389150. DOI:10.1155/2014/389150 · 2.71 Impact Factor
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ABSTRACT: The classical complement pathway is initiated by the large (~800 kDa) and flexible multimeric C1 complex. Its catalytic function is triggered by the proteases hetero-tetramer C1r2s2, which is associated to the C1q sensing unit, a complex assembly of 18 chains built as a hexamer of heterotrimers. Initial pioneering studies gained insights into the main architectural principles of the C1 complex. A dissection strategy then provided the high-resolution structures of its main functional and/or structural building blocks, as well as structural details on some key protein-protein interactions. These past and current discoveries will be briefly summed up in order to address the question of what is still ill-defined. On a functional point of view, the main molecular determinants of C1 activation and its tight control will be delineated. The current perspective remains to decipher how C1 really works and is controlled in vivo, both in normal and pathological settings.Frontiers in Immunology 01/2014; 5:565. DOI:10.3389/fimmu.2014.00565