Structural insights into secretory immunoglobulin A and its interaction with a pneumococcal adhesin

Abstract

<jats:title>Abstract</jats:title><jats:p>Secretory Immunoglobulin A (SIgA) is the most abundant antibody at the mucosal surface. SIgA possesses two additional subunits besides IgA: the joining chain (J-chain) and secretory component (SC). SC is the ectodomain of the polymeric immunoglobulin receptor (pIgR), which functions to transport IgA to the mucosa. The underlying mechanism of how the J-chain and pIgR/SC facilitates the assembly and secretion of SIgA remains to be understood. During the infection of <jats:italic>Streptococcus pneumoniae</jats:italic>, a pneumococcal adhesin SpsA hijacks SIgA and unliganded pIgR/SC to evade host defense and gain entry to human cells. How SpsA specifically targets SIgA and pIgR/SC also remains unclear. Here we report a cryo-electron microscopy structure of the Fc region of human IgA1 (Fcα) in complex with J-chain and SC (Fcα-J-SC), which reveals the organization principle of SIgA. We also present the structure of Fcα-J-SC in complex with SpsA, which uncovers the specific interaction between SpsA and human pIgR/SC. These results advance the molecular understanding of SIgA and shed light on the pathogenesis of <jats:italic>S. pneumoniae</jats:italic>.</jats:p>

The structures of secretory and dimeric immunoglobulin A

“…However, the majority of interfacing residues appear to be conserved (Figure 1-figure supplement 1B). Consistent with these observations, comparison of our mouse SIgA with structures of dimeric forms of the human SIgA1 core (no Fabs), reported in the same timeframe as this work (Kumar, Arthur et al 2020, Wang, Wang et al 2020 revealed largely superimposable structures with some variability in contacts between complex components (not shown). The modeled positions of SC D2 are variable among structures, likely due to inherent flexibility in the domain's position, however, the structures have similar angles of bend (99 o in human SIgA and 97 o in mouse SIgA) and tilt (31 o in human SIgA and to 30 o tilt in mouse SIgA).…”

“…Yet without the structures of the JC, dIgA and SIgA, interpreting biological data, understanding functional mechanisms and designing IgA-based therapeutics has remained a challenge. Our structures and related, human IgA structures published in the same timeframe as this work (Kumar, Arthur et al 2020, Wang, Wang et al 2020 provide an opportunity to addresses many outstanding questions surrounding SIgA and its functions as a mucosal antibody; we discuss a subset of them below and provide a model for formation, transport and function of SIgA in mammals.…”

Structural basis for Fc receptor recognition of immunoglobulin M

“…The Ig-like domain is responsible for ligand binding 3 and shares about 40% sequence identity with the first Ig-like domain of polymeric immunoglobulin receptor (pIgR-D1), which is encoded by a gene located in the same chromosomal region in mammals 2 . However, rather than binding to both polymeric IgM and IgA as pIgR does 4–7 , FcμR exclusively binds to IgM 8 , indicating its specific binding mechanisms as well as functional roles. Potential residues responsible for the binding between IgM and FcμR have been proposed but the structure of the FcμR/IgM complex is currently unknown 9–11 .…”

Perspective Chapter: Engineering Secretory IgA against Infectious Diseases

“…It is the predominant antibody found in the mucosa-a vast extracellular environment constantly exposed to antigens from both pathogens and commensal bacteria-where it is secreted in the form of secretory IgA (SIgA). This is a multicomponent molecule comprised of two IgA monomers linked together by a joining chain (J chain) and covalently attached to the secretory component (SC) [2]. The secretory component wraps around the antibody complex and confers resistance to proteolytic degradation, along with protection in low pH environments.…”