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C1q Binds Phosphatidylserine and Likely Acts as a Multiligand-Bridging Molecule in Apoptotic Cell Recognition¹

Helena Païdassi^*, Pascale Tacnet-Delorme^*, Virginie Garlatti, Claudine Darnault, Berhane Ghebrehiwet, Christine Gaboriaud, Gérard J. Arlaud^* and Philippe Frachet^2,*

^* Laboratoire d’Enzymologie Moléculaire and Laboratoire de Cristallographie et Cristallogénèse des Protéines, Institut de Biologie Structurale, Jean-Pierre Ebel (Unité Mixte de Recherche 5075), Commissariat à l’Energie Atomique, Centre National de la Recherche Scientifique, Université Joseph Fourier, Grenoble, France; and Department of Medicine, Health Sciences Center, State University of New York, Stony Brook, NY 11794

Efficient apoptotic cell clearance is critical for maintenance of tissue homeostasis, and to control the immune responses mediated by phagocytes. Little is known about the molecules that contribute "eat me" signals on the apoptotic cell surface. C1q, the recognition unit of the C1 complex of complement, also senses altered structures from self and is a major actor of immune tolerance. HeLa cells were rendered apoptotic by UV-B treatment and a variety of cellular and molecular approaches were used to investigate the nature of the target(s) recognized by C1q. Using surface plasmon resonance, C1q binding was shown to occur at early stages of apoptosis and to involve recognition of a cell membrane component. C1q binding and phosphatidylserine (PS) exposure, as measured by annexin V labeling, proceeded concomitantly, and annexin V inhibited C1q binding in a dose-dependent manner. As shown by cosedimentation, surface plasmon resonance, and x-ray crystallographic analyses, C1q recognized PS specifically and avidly (K_D = 3.7–7 x 10^–8 M), through multiple interactions between its globular domain and the phosphoserine group of PS. Confocal microscopy revealed that the majority of the C1q molecules were distributed in membrane patches where they colocalized with PS. In summary, PS is one of the C1q ligands on apoptotic cells, and C1q-PS interaction takes place at early stages of apoptosis, in newly organized membrane patches. Given its versatile recognition properties, these data suggest that C1q has the unique ability to sense different markers which collectively would provide strong eat me signals, thereby allowing efficient apoptotic cell removal.

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¹ The atomic coordinates presented in this article have been deposited in the Protein Data Bank with the accession codes 2jG8 and 2jG9.

² Address correspondence and reprint requests to Dr. Philippe Frachet, Laboratoire d’Enzymologie Moléculaire, Institut de Biologie Structurale, Jean-Pierre Ebel, 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France. E-mail address: philippe.frachet{at}ibs.fr

³ Abbreviations used in this paper: DC, dendritic cell; PS, phosphatidylserine; GR, globular region; PC, phosphatidylcholine; SPR, surface plasmon resonance; FSC, forward scattering; SSC, side scattering; PI, propidium iodide.