PMID- 34155115
OWN - NLM
STAT- MEDLINE
DCOM- 20211203
LR  - 20211214
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 118
IP  - 26
DP  - 2021 Jun 29
TI  - C1q binding to surface-bound IgG is stabilized by C1r(2)s(2) proteases.
LID - 10.1073/pnas.2102787118 [doi]
LID - e2102787118
AB  - 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 
      (C1qr(2)s(2)) consists of the large recognition protein C1q and a heterotetramer 
      of proteases C1r and C1s (C1r(2)s(2)). While interactions between C1 and IgG-Fc 
      are believed to be mediated by the globular heads of C1q, we here find that 
      C1r(2)s(2) 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 C1r(2)s(2) 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 
      C1r(2)s(2) 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.
CI  - Copyright (c) 2021 the Author(s). Published by PNAS.
FAU - Zwarthoff, Seline A
AU  - Zwarthoff SA
AUID- ORCID: 0000-0002-4395-2007
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands.
FAU - Widmer, Kevin
AU  - Widmer K
AD  - Pharmaceutical Sciences, University of Basel, 4001 Basel, Switzerland.
FAU - Kuipers, Annemarie
AU  - Kuipers A
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands.
FAU - Strasser, Jurgen
AU  - Strasser J
AUID- ORCID: 0000-0002-9722-702X
AD  - Nano Structuring and Bio-Analytics Group, TIMed Center, of Applied Sciences Upper 
      Austria, 4020 Linz, Austria.
FAU - Ruyken, Maartje
AU  - Ruyken M
AUID- ORCID: 0000-0003-2289-3412
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands.
FAU - Aerts, Piet C
AU  - Aerts PC
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands.
FAU - de Haas, Carla J C
AU  - de Haas CJC
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands.
FAU - Ugurlar, Deniz
AU  - Ugurlar D
AUID- ORCID: 0000-0001-8841-3851
AD  - Structural Biochemistry, Bijvoet Center for Biomolecular Research, Utrecht 
      University, 3584 CH Utrecht, The Netherlands.
FAU - den Boer, Maurits A
AU  - den Boer MA
AUID- ORCID: 0000-0002-2608-9395
AD  - Biomolecular Mass Spectrometry & Proteomics, Bijvoet Center for Biomolecular 
      Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 
      3584 CH Utrecht, The Netherlands.
AD  - Netherlands Proteomics Center, 3584 CH, Utrecht, The Netherlands.
FAU - Vidarsson, Gestur
AU  - Vidarsson G
AD  - Experimental Immunohematology, Sanquin Research, 1066 CX Amsterdam, The 
      Netherlands.
FAU - van Strijp, Jos A G
AU  - van Strijp JAG
AUID- ORCID: 0000-0001-6253-0830
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands.
FAU - Gros, Piet
AU  - Gros P
AUID- ORCID: 0000-0002-7782-2585
AD  - Structural Biochemistry, Bijvoet Center for Biomolecular Research, Utrecht 
      University, 3584 CH Utrecht, The Netherlands.
FAU - Parren, Paul W H I
AU  - Parren PWHI
AD  - Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA 
      Leiden, The Netherlands.
AD  - Lava Therapeutics, 3584 CM Utrecht, The Netherlands.
FAU - van Kessel, Kok P M
AU  - van Kessel KPM
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands.
FAU - Preiner, Johannes
AU  - Preiner J
AUID- ORCID: 0000-0002-6755-6543
AD  - Nano Structuring and Bio-Analytics Group, TIMed Center, of Applied Sciences Upper 
      Austria, 4020 Linz, Austria.
FAU - Beurskens, Frank J
AU  - Beurskens FJ
AD  - Genmab, 3584 CT Utrecht, The Netherlands.
FAU - Schuurman, Janine
AU  - Schuurman J
AUID- ORCID: 0000-0002-9738-9926
AD  - Genmab, 3584 CT Utrecht, The Netherlands.
FAU - Ricklin, Daniel
AU  - Ricklin D
AUID- ORCID: 0000-0001-6140-0233
AD  - Pharmaceutical Sciences, University of Basel, 4001 Basel, Switzerland.
FAU - Rooijakkers, Suzan H M
AU  - Rooijakkers SHM
AUID- ORCID: 0000-0003-4102-0377
AD  - Medical Microbiology, University Medical Center Utrecht, Utrecht University, 3584 
      CX Utrecht, The Netherlands; S.H.M.Rooijakkers@umcutrecht.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Immunoglobulin G)
RN  - 80295-33-6 (Complement C1q)
RN  - EC 3.4.21.41 (Complement C1r)
RN  - EC 3.4.21.42 (Complement C1s)
SB  - IM
MH  - Cell Membrane/*metabolism
MH  - Complement Activation
MH  - Complement C1q/*metabolism
MH  - Complement C1r/*metabolism
MH  - Complement C1s/*metabolism
MH  - Humans
MH  - Immunoglobulin G/*metabolism
MH  - Microscopy, Atomic Force
MH  - Mutation/genetics
MH  - Phagocytosis
MH  - Protein Binding
MH  - Protein Multimerization
MH  - Protein Stability
MH  - Staphylococcus aureus/immunology
PMC - PMC8256010
OTO - NOTNLM
OT  - C1
OT  - IgG hexamerization
OT  - IgG subclasses
OT  - Staphylococcus aureus
OT  - complement
COIS- Competing interest statement: A.K., J.A.G.v.S., P.W.H.I.P., K.P.M.v.K., F.J.B., 
      J. Schuurman, and S.H.M.R. are coinventors on a patent describing antibody 
      therapies against S. aureus.
EDAT- 2021/06/23 06:00
MHDA- 2021/12/15 06:00
PMCR- 2021/06/21
CRDT- 2021/06/22 05:54
PHST- 2021/06/22 05:54 [entrez]
PHST- 2021/06/23 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2021/06/21 00:00 [pmc-release]
AID - 2102787118 [pii]
AID - 202102787 [pii]
AID - 10.1073/pnas.2102787118 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):e2102787118. doi: 
      10.1073/pnas.2102787118.