Publication: Identification of potential C1-binding sites in the immunoglobulin C<inf>L</inf> domains
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Issued Date
2024-08-01
Resource Type
ISSN
09538178
eISSN
14602377
Scopus ID
2-s2.0-85198681835
Pubmed ID
38564192
Journal Title
International Immunology
Volume
36
Issue
8
Start Page
405
End Page
411
Rights Holder(s)
SCOPUS
Bibliographic Citation
International Immunology Vol.36 No.8 (2024) , 405-411
Suggested Citation
Yanaka S., Kodama A., Nishiguchi S., Fujita R., Shen J., Boonsri P., Sung D., Isono Y., Yagi H., Miyanoiri Y., Uchihashi T., Kato K. Identification of potential C1-binding sites in the immunoglobulin C<inf>L</inf> domains. International Immunology Vol.36 No.8 (2024) , 405-411. 411. doi:10.1093/intimm/dxae017 Retrieved from: https://hdl.handle.net/20.500.14740/20402
Corresponding Author(s)
Other Contributor(s)
Abstract
Immunoglobulin G (IgG) molecules that bind antigens on the membrane of target cells spontaneously form hexameric rings, thus recruiting C1 to initiate the complement pathway. However, our previous report indicated that a mouse IgG mutant lacking the Cγ1 domain activates the pathway independently of antigen presence through its monomeric interaction with C1q via the CL domain, as well as Fc. In this study, we investigated the potential interaction between C1q and human CL isoforms. Quantitative single-molecule observations using high-speed atomic force microscopy revealed that human Cκ exhibited comparable C1q binding capabilities with its mouse counterpart, surpassing the Cλ types, which have a higher isoelectric point than the Cκ domains. Nuclear magnetic resonance and mutation experiments indicated that the human and mouse Cκ domains share a common primary binding site for C1q, centred on Glu194, a residue conserved in the Cκ domains but absent in the Cλ domains. Additionally, the Cγ1 domain, with its high isoelectric point, can cause electrostatic repulsion to the C1q head and impede the C1q-interaction adjustability of the Cκ domain in Fab. The removal of the Cγ1 domain is considered to eliminate these factors and thus promote Cκ interaction with C1q with the potential risk of uncontrolled activation of the complement pathway in vivo in the absence of antigen. However, this research underscores the presence of potential subsites in Fab for C1q binding, offering promising targets for antibody engineering to refine therapeutic antibody design.