The structures of secretory and dimeric immunoglobulin A.

Sonya Kumar Bharathkar,Benjamin W Parker,Andrey G Malyutin,Kathryn E Huey-Tubman,Beth M Stadtmueller,Emad Tajkhorshid,Nandan Haloi

doi:10.7554/elife.56098

Sonya Kumar Bharathkar, Benjamin W Parker + Show 5 more

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https://doi.org/10.7554/elife.56098

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Abstract

Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody, which binds pathogens and commensal microbes. SIgA is a polymeric antibody, typically containing two copies of IgA that assemble with one joining-chain (JC) to form dimeric (d) IgA that is bound by the polymeric Ig-receptor ectodomain, called secretory component (SC). Here, we report the cryo-electron microscopy structures of murine SIgA and dIgA. Structures reveal two IgAs conjoined through four heavy-chain tailpieces and the JC that together form a β-sandwich-like fold. The two IgAs are bent and tilted with respect to each other, forming distinct concave and convex surfaces. In SIgA, SC is bound to one face, asymmetrically contacting both IgAs and JC. The bent and tilted arrangement of complex components limits the possible positions of both sets of antigen-binding fragments (Fabs) and preserves steric accessibility to receptor-binding sites, likely influencing antigen binding and effector functions.

Highlights

The vertebrate mucosa is a vast extracellular environment that mediates host interactions with a broad range of antigens including toxins, pathogens, and commensal organisms
The CH2-CH3 domains in both Fcs aligned with the published monomeric IgA Fc structure lacking the Tp (Herr et al, 2003); despite shared sequences, the four IgA heavy chains formed structurally unique contacts with the joining chain (JC) and secretory component (SC)
Potential N-linked glycosylation sites (PNGS) are distributed throughout the complex; the seven, PNGS located on SC, are clustered on the front face of Secretory Immunoglobin A (SIgA) (Figure 2)

Summary

Introduction

The vertebrate mucosa is a vast extracellular environment that mediates host interactions with a broad range of antigens including toxins, pathogens, and commensal organisms. The diversity of these antigens, some of which are beneficial to the host and some of which are harmful, has driven complex evolutionary interplay between mucosal immune system molecules and mucosal antigens, resulting in antibodies with novel structural and functional mechanisms compared to circulatory counterparts (Flajnik, 2010; Kaetzel, 2014). SIgA functions are thought to be dominated by physical mechanisms including coating, cross-linking, agglutination, and enchained growth of mucosal antigens; outcomes are diverse and, typically, not associated with inflammation (Woof and Russell, 2011; Pabst and Slack, 2020).

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