C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases

Seline A. Zwarthoff, Kevin Widmer, Annemarie Kuipers, Jürgen Strasser, Maartje Ruyken, Piet C. Aerts, Carla J.C. de Haas, Deniz Ugurlar, Gestur Vidarsson, Jos A. G. Van Strijp, Piet Gros, Paul W.H.I. Parren, Kok P.M. van Kessel, Johannes Preiner, Frank J. Beurskens, Janine Schuurman, Daniel Ricklin, Suzan H.M. Rooijakkers

Research output: Contribution to journalArticlepeer-review

Abstract

Complement is an important effector mechanism for antibodymediated clearance of infections and tumor cells. Upon binding to target cells, the antibody's constant (Fc) domain recruits complement component C1 to initiate a proteolytic cascade that generates lytic pores and stimulates phagocytosis. The C1 complex (C1qr2s2) consists of the large recognition protein C1q and a heterotetramer of proteases C1r and C1s (C1r2s2). While interactions between C1 and IgG-Fc are believed to be mediated by the globular heads of C1q, we here find that C1r2s2 proteases affect the capacity of C1q to form an avid complex with surface-bound IgG molecules (on various 2,4-dinitrophenol [DNP]-coated surfaces and pathogenic Staphylococcus aureus). The extent to which C1r2s2 contributes to C1q-IgG stability strongly differs between human IgG subclasses. Using antibody engineering of monoclonal IgG, we reveal that hexamer-enhancing mutations improve C1q-IgG stability, both in the absence and presence of C1r2s2. In addition, hexamer-enhanced IgGs targeting S. aureus mediate improved complement-dependent phagocytosis by human neutrophils. Altogether, these molecular insights into complement binding to surface-bound IgGs could be important for optimal design of antibody therapies.

Original languageEnglish
Article numbere2102787118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number26
DOIs
Publication statusPublished - 29 Jun 2021

Keywords

  • C1
  • Complement
  • IgG hexamerization
  • IgG subclasses
  • Staphylococcus aureus

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