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

Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2102787118. doi: 10.1073/pnas.2102787118.


Complement is an important effector mechanism for antibody-mediated 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.

Keywords: C1; IgG hexamerization; IgG subclasses; Staphylococcus aureus; complement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / metabolism*
  • Complement Activation
  • Complement C1q / metabolism*
  • Complement C1r / metabolism*
  • Complement C1s / metabolism*
  • Humans
  • Immunoglobulin G / metabolism*
  • Microscopy, Atomic Force
  • Mutation / genetics
  • Phagocytosis
  • Protein Binding
  • Protein Multimerization
  • Protein Stability
  • Staphylococcus aureus / immunology


  • Immunoglobulin G
  • Complement C1q
  • Complement C1r
  • Complement C1s