8xkk

Publication Abstract from PubMed

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 Cgamma1 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 Ckappa exhibited comparable C1q binding capabilities with its mouse counterpart, surpassing the Clambda types, which have a higher isoelectric point than the Ckappa domains. Nuclear magnetic resonance and mutation experiments indicated that the human and mouse Ckappa domains share a common primary binding site for C1q, centred on Glu194, a residue conserved in the Ckappa domains but absent in the Clambda domains. Additionally, the Cgamma1 domain, with its high isoelectric point, can cause electrostatic repulsion to the C1q head and impede the C1q-interaction adjustability of the Ckappa domain in Fab. The removal of the Cgamma1 domain is considered to eliminate these factors and thus promote Ckappa 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.

Identification of potential C1-binding sites in the immunoglobulin CL domains.,Yanaka S, Kodama A, Nishiguchi S, Fujita R, Shen J, Boonsri P, Sung D, Isono Y, Yagi H, Miyanoiri Y, Uchihashi T, Kato K Int Immunol. 2024 Jul 13;36(8):405-412. doi: 10.1093/intimm/dxae017. PMID:38564192^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.