Abstract
As a first-line vertebrate immune defense, the polymeric immunoglobulin receptor (pIgR) transports polymeric IgA and IgM across epithelia to mucosal secretions, where the cleaved ectodomain (secretory component; SC) becomes a component of secretory antibodies, or when unliganded, binds and excludes bacteria. Here we report the 2.6Å crystal structure of unliganded human SC (hSC) and comparisons with a 1.7Å structure of teleost fish SC (tSC), an early pIgR ancestor. The hSC structure comprises five immunoglobulin-like domains (D1-D5) arranged as a triangle, with an interface between ligand-binding domains D1 and D5. Electron paramagnetic resonance measurements confirmed the D1-D5 interface in solution and revealed that it breaks upon ligand binding. Together with binding studies of mutant and chimeric SCs, which revealed domain contributions to secretory antibody formation, these results provide detailed models for SC structure, address pIgR evolution, and demonstrate that SC uses multiple conformations to protect mammals from pathogens.
Highlights
The mucosa is fundamental to vertebrate survival, forming an elaborate extracellular environment, in which the immune system mediates host interactions with commensal and pathogenic agents
We characterized the conformation and dynamics of free and liganded human SC (hSC) in solution, and used structure-based alignments to create mutant and chimeric SCs to determine how individual domains contribute to ligand binding. These results provide a detailed model for SC structure and polymeric immunoglobulin (pIg) binding mechanisms, demonstrating that mammalian SC evolved to adopt a compact, closed triangular structure, which opens upon ligand binding, whereas two-domain SC ancestors consist of tandem domains arranged in an elongated conformation
Since the discovery of SC (Tomasi et al, 1965) and later identification of its membrane-bound form (Mostov et al, 1980), the polymeric Immunoglobulin receptor (pIgR) has been established as a central component of the vertebrate immune response, transporting and stabilizing secretory antibodies, excluding pathogenic bacteria, providing immune protection at epithelial barriers such as the lungs, gut, urogenital tract, and conferring protection to offspring through breast milk (Kaetzel, 2005)
Summary
The mucosa is fundamental to vertebrate survival, forming an elaborate extracellular environment, in which the immune system mediates host interactions with commensal and pathogenic agents. The human mucosa protects ~400 m2 of epithelial barriers in the gut, lungs, urogenital tract, and associated tissues such as mammary glands. Protection is conferred largely through the function of the polymeric Immunoglobulin receptor (pIgR), which transports and stabilizes secretory antibodies and functions as an innate immune factor (Kaetzel, 2005). Human pIgR is a glycosylated type I membrane protein consisting of a 620-residue ectodomain with five tandem immunoglobulin-like (Ig-like) domains, a 23-residue transmembrane domain, and a 103-residue intracellular domain (Hamburger et al, 2006) (Figure 1A). PIgR is the oldest identifiable Fc receptor, first emerging in teleost (bony) fish. Throughout evolution, the number of Ig-like domains in the pIgR ectodomain increased; typically, bony fish express a two-domain variant, birds, amphibians and reptiles a fourdomain variant, and mammals a five-domain variant (D1-D5) (Akula et al, 2014). Mammals, including rabbits and cows, express an alternatively-spliced variant containing D1, D4 and D5 (Deitcher and Mostov, 1986; Kulseth et al, 1995)
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