The Structures of Secretory and Dimeric Immunoglobulin A

Abstract

Secretory (S) Immunoglobulin (I) 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 joiningchain (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.

Structure of the human secretory immunoglobulin M core

“…Furthermore, the structures revealed that the SC undergoes a large conformational rearrangement from a closed, apo state (Stadtmueller et al, 2016), to an open, extended conformation upon polymeric IgA binding. Our structures are highly consistent with two additional reported structures of murine (Kumar Bharathkar et al, 2020) and human sIgA (Wang et al, 2020).…”

CD5L associates with IgM via the J chain

“…Recent structural insights from our research and others have revealed the molecular mechanism of the J chain in promoting IgM and IgA polymerization, as well as its role in the recognition of IgM and IgA by pIgR 30,31,[33][34][35] . In this study and another study 42 , we further demonstrate that the J chain also plays a crucial role in mediating the interaction between the IgM pentamer and CD5L, as well as between systemic IgA and FcRL4.…”

“…2b). It is worth noting that this hairpin structure, observable in IgA structures [33][34][35] , was disordered in all previous IgM structures without CD5L. In SRCR2, K173 and R183 interact with E77J and E75J (J chain residues are denoted by subscripts), respectively; whereas V185-T187 pack with N80J-I82J.…”

Suppression of epithelial proliferation and tumourigenesis by immunoglobulin A

“…PIgR is localized to the basolateral side of epithelial cells and moreover cannot bind secretory IgA, making it unlikely to be involved in IgA feedback signaling to the epithelium. In secretory IgA, the Fc portion of the antibody is partially obscured by the SC 70 , and colon epithelial cells do not express a typical Fc receptor that binds the alpha heavy chain. However, many proteins have reported interactions with IgA, leaving open the possibility of a non-conventional antibody receptor being responsible for such epithelial feedback.…”