The two domains are related by ~118 and share a small interface (596 2total buried surface area) involving residues in the D3 A and B strands and the D4 C-C loop

The two domains are related by ~118 and share a small interface (596 2total buried surface area) involving residues in the D3 A and B strands and the D4 C-C loop. mammals from pathogens. DOI:http://dx.doi.org/10.7554/eLife.10640.001 Research Organism:Human == eLife digest == A sticky substance called mucus lines our airways and gut, where it acts as a physical barrier to prevent bacteria and other microbes from entering the body. Mucus also contains proteins called antibodies that can bind to and neutralize molecules from microbes (known as antigens). The primary antibody found in mucus is called Immunoglobulin A. This antibody is produced by immune cells within the body and must pass through the epithelial cells that line the airway or gut to reach the layer of mucus. K+ Channel inhibitor These epithelial cells have a receptor protein called the polymeric immunoglobulin receptor (plgR) that binds to Immunoglobulin A molecules, transports them across the cell, and then releases them into the mucus layer. The pIgR also releases Immunoglobulin A into breast milk, which protects nursing infants until their own immune system has developed. When released into the mucus layer, the Immunoglobulin A antibodies remain attached to a portion of pIgR known as the secretory component. This part of the receptor serves to stabilize and protect the antibodies from being degraded and helps the antibodies to bind to other host and bacterial proteins. Researchers have noted that the secretory component can be released into the mucus even when it is not attached to an antibody. These free secretory components have been shown to help prevent bacteria and the toxins they produce K+ Channel inhibitor from entering the body. Despite the importance of secretory component in immune responses, the three-dimensional structure of the secretory component and how it interacts with antibodies and bacteria remained unknown. Here, Stadtmueller et al. use a technique called X-ray crystallography to determine a three-dimensional model of the free form of a secretory component from humans, and compare it to an ancestral secretory component protein found in fish. Further experiments on the human protein revealed how the structure of the secretory component changes when antibodies bind to it. Stadtmueller et al. propose a model for how both forms of the secretory component can protect the body from microbes and other external agents. The next challenge is to develop a three-dimensional model of the secretory component when it is bound to Immunoglobulin A. DOI:http://dx.doi.org/10.7554/eLife.10640.002 == Introduction == 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 m2of 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 also 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 K+ Channel inhibitor ectodomain increased; typically, bony fish express a two-domain variant, birds, amphibians and reptiles a four-domain 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). == Figure 1. Structure of hSC. == (A) Schematic of mature human pIgR protein indicating Ig-domain (D1-D5) boundaries. The proteolytic cut site that releases hSC from the apical membrane (black arrow), the 23-residue transmembrane region (TM), cytoplasmic tail, and potentialN-linked glycosylation sites (PNGS, orange arrows) are indicated. (B) Schematic epithelial cell layer showing basolateral to apical transcytosis (arrows) of pIgR and release of free SC, SIgA, and SIgM. (C) Cartoon representation of the hSC structure viewed from the front face colored to highlight CDR loops (green), D5 Cys468 and Cys502 (yellow), PNGS (orange), domain linkers (grey), and hSC termini (N-terminus: blue sphere; C-terminus: red sphere). (D) Molecular surface representation of the hSC structure shown in six orientations and colored as in (C). DOI:http://dx.doi.org/10.7554/eLife.10640.003 The pIgR is expressed on the basolateral surface of epithelial RGS1 cells where the ectodomain binds polymeric forms of IgA and IgM produced by local plasma cells. Similar.