IMMUNOLOGY
Structure of the secretory immunoglobulin A core
Nikit Kumar, Christopher P. Arthur, Claudio Ciferri, Marissa L. Matsumoto
Secretory immunoglobulin A (sIgA) represents the immune system’s first line of defense against
mucosal pathogens. IgAs are transported across the epithelium, as dimers and higher-order polymers,
by the polymeric immunoglobulin receptor (pIgR). Upon reaching the luminal side, sIgAs mediate
host protection and pathogen neutralization. Inrecent years, an increasing amount of attention
has been given to IgA as a novel therapeutic antibody. However, despite extensive studies, sIgA
structures have remained elusive. Here, we determine the atomic resolution structures of dimeric,
tetrameric, and pentameric IgA-Fc linked by the joining chain (JC) and in complex with the secretory
component of the pIgR. We suggest a mechanism in which the JC templates IgA oligomerization
and imparts asymmetry for pIgR binding and transcytosis. This framework will inform the design of
future IgA-based therapeutics.
S
ecreted polymeric immunoglobulins A
and M (pIgA and pIgM, respectively) play
vital roles in protecting the ~400 m^2 of
human mucosa from invasion by patho-
gens. IgA and IgM contain 18-residue tail-
piece extensions on their heavy chains that
bestow polymer-forming capabilities ( 1 ). IgM
can independently oligomerize to form hex-
amers, whereas IgA polymerization requires
the 137-residue joining chain (JC), a protein
with no known structural homologs ( 2 ). The
predominant IgA oligomer is a dimer, though
a smaller fraction of higher-order polymers up
to pentamers have been described ( 1 ). At the
core of pIgA is a JC-clasped, tail-to-tail dimer
stabilized by two disulfides between the JC
and one tailpiece of each monomer ( 3 ). Addi-
tional monomers are linked to this precursor
via tailpiece-to-tailpiece–mediated disulfides
( 3 , 4 ). Although less abundant than the dimer,
higher-order polymers display better neutral-
izing capabilities, specifically for low-affinity
antigens ( 5 ).
The pIgA that is synthesized by mucosal
plasma cells undergoes transcytosis, crossing
the epithelium to reach the external secretions
and perform its protective function. To initiate
this process, pIgA binds the ectodomain of
basolaterally expressed pIg receptor (pIgR),
an interaction that requires the JC and is
stabilized through a disulfide bond between
the receptor and one Fc ( 6 ). Once bound, the
receptor and pIgA undergotranscytosis through
the epithelial cell to the mucosa. Upon trans-
cytosis, proteolytic cleavage by unidentified
protease(s) releases the secretory component
(SC) of the receptor, which remains covalently
attached to pIgA to form secretory IgA (sIgA)
( 7 , 8 ). In this mature form, sIgA performs its
antimicrobial, neutralization, and protective
functions ( 8 ).
In recent years, extensive efforts have been
made to develop vaccines that induce immu-
nity via the mucosal route by eliciting sIgA
responses ( 1 ). In the field of biotechnology, a
major focus has been to engineer antibodies
to target disease-relevant tissues, and ther-apeutic IgAs may allow delivery to mucosal
tissues inaccessible to traditional IgG-based
therapeutics ( 1 ). Thus, a detailed structural
characterization of sIgA is critical for the
development of future therapeutics and
vaccines.
In this study, we use cryo–electron micros-
copy (cryo-EM) to determine the architecture
of sIgA-Fc dimers, tetramers, and pentamers
at atomic resolution. We propose a mech-
anism of JC-templated IgA oligomerization
and describe a model for pIgR recognition.
These findings will inform the design of un-
explored IgA-based therapeutics with the po-
tential for tissue-specific targeting and mucosal
delivery.Reconstitution of sIgA complexes
Previous cryo-EM studies of pIgA indicated
that these molecules are refractory to high-
resolution structure determination due to
the inherent flexibility of the hinge regions
as well as the tailpieces interconnecting mono-
mers ( 9 ). We therefore reasoned that truncationRESEARCH
Kumaret al.,Science 367 , 1008–1014 (2020) 28 February 2020 1of7
Department of Structural Biology, Genentech, Inc., South
San Francisco, CA, USA 94080.
*Corresponding author. Email: [email protected] (C.C.);
[email protected] (M.L.M.)
Fig. 1. Cryo-EM structure of dimeric sIgA1.(A) Top, back, and front view schematics of subunit arrangements
in the dimer. (B) Cryo-EM reconstruction of dimeric sIgA1. Transparent maps overlaid with the model are shown.