8xlb
Clamda3 domain of human immunoglobulin
Structural highlights
FunctionIGLC3_HUMAN Constant region of immunoglobulin light chains. Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:20176268, PubMed:22158414). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:17576170, PubMed:20176268).[1] [2] [3] Publication Abstract from PubMedImmunoglobulin 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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