Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Quantitative Visualization of the Interaction between Complement Component C1 and Immunoglobulin G: The Effect of CH1 Domain Deletion

Saeko Yanaka
ORCID logo ,
Shigetaka Nishiguchi
,
Rina Yogo
,
Hiroki Watanabe
,
Jiana Shen
,
Hirokazu Yagi
,
Takayuki Uchihashi
* ORCID logo ,
and Koichi Kato
* ORCID logo
Version 1 : Received: 28 December 2021 / Approved: 31 December 2021 / Online: 31 December 2021 (10:36:38 CET)

A peer-reviewed article of this Preprint also exists.

Yanaka, S.; Nishiguchi, S.; Yogo, R.; Watanabe, H.; Shen, J.; Yagi, H.; Uchihashi, T.; Kato, K. Quantitative Visualization of the Interaction between Complement Component C1 and Immunoglobulin G: The Effect of CH1 Domain Deletion. Int. J. Mol. Sci. 2022, 23, 2090. Yanaka, S.; Nishiguchi, S.; Yogo, R.; Watanabe, H.; Shen, J.; Yagi, H.; Uchihashi, T.; Kato, K. Quantitative Visualization of the Interaction between Complement Component C1 and Immunoglobulin G: The Effect of CH1 Domain Deletion. Int. J. Mol. Sci. 2022, 23, 2090.

Abstract

Immunoglobulin G (IgG) adopts a modular multidomain structure that mediates antigen recognition and effector functions, such as complement-dependent cytotoxicity. IgG molecules are self-assembled into a hexameric ring on antigen-containing membranes, recruiting the complement component, C1q. To provide deeper insights into the initial step of the complement pathway, we report a high-speed atomic force microscopy study for quantitative visualization of the interaction between IgG and the C1 complex composed of C1q, C1r, and C1s. Results showed that C1q in the C1 complex is restricted regarding internal motion and has a stronger binding affinity for on-membrane IgG assemblages than C1q alone, presumably because of smaller conformational entropy loss upon binding. Furthermore, we visualized a 1:1 stoichiometric interaction between C1/C1q and an IgG variant that lacks the entire CH1 domain in the absence of antigen. In addition to the canonical C1q-binding site on Fc, their interactions are mediated through a secondary site on the CL domain that is cryptic in the presence of the CH1 domain. Our findings offer clues for novel-modality therapeutic antibodies.

Keywords

immunoglobulin G; complement component C1; high-speed atomic force microscopy; CH1; CL

Subject

Biology and Life Sciences, Biophysics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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