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DOI	10.1073/pnas.2102787118
	C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases
	Zwarthoff S.A.; Widmer K.; Kuipers A.; Strasser J.; Ruyken M.; Aerts P.C.; de Haas C.J.C.; Ugurlar D.; den Boer M.A.; Vidarsson G.; van Strijp J.A.G.; Gros P.; Parren P.W.H.I.; van Kessel K.P.M.; Preiner J.; Beurskens F.J.; Schuurman J.; Ricklin D.; Rooijakkers S.H.M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:26
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	C1; Complement; IgG hexamerization; IgG subclasses; Staphylococcus aureus
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238881
作者单位	Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, 3584 CX, Netherlands; Pharmaceutical Sciences, University of Basel, Basel, 4001, Switzerland; Nano Structuring and Bio-Analytics Group, TIMed Center of Applied Sciences Upper Austria, Linz, 4020, Austria; Structural Biochemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, 3584 CH, Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CH, Netherlands; Netherlands Proteomics Center, Utrecht, 3584 CH, Netherlands; Experimental Immunohematology, Sanquin Research, Amsterdam, 1066 CX, Netherlands; Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands; Lava Therapeutics, Utrecht, 3584 CM, Netherlands; Genmab, Utrecht, 3584 CT, Netherlands
推荐引用方式 GB/T 7714	Zwarthoff S.A.,Widmer K.,Kuipers A.,et al. C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases[J],2021,118(26).
APA	Zwarthoff S.A..,Widmer K..,Kuipers A..,Strasser J..,Ruyken M..,...&Rooijakkers S.H.M..(2021).C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases.Proceedings of the National Academy of Sciences of the United States of America,118(26).
MLA	Zwarthoff S.A.,et al."C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases".Proceedings of the National Academy of Sciences of the United States of America 118.26(2021).