The amino-terminal domain of rabbit secretory component is responsible for noncovalent binding to immunoglobulin A dimers.

Frutiger, Séverine; Hughes, Graham J.; Hanly, W. Carey; Kingzette, M; Jaton, Jean‐Claude

doi:10.1016/s0021-9258(18)66618-9

Cited by 71 publications

(12 citation statements)

References 37 publications

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“…The D1 domain is the major binding site, and the three loops that are analogous to the complementarity-determining regions (CDRs) of immunoglobulin variable domains are all involved (Fig. 4A) (19)(20)(21)(22). In the ligand-free state of pIgR/SC, D1 to D5 are arranged in the form of an isosceles triangle (22), with the D2-D3 and D4-D5 sides having similar lengths (Fig.…”

Section: Researchmentioning

confidence: 99%

Structural insights into immunoglobulin M

Wang

et al. 2020

Science

100

132

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Immunoglobulin M (IgM) plays a pivotal role in both humoral and mucosal immunity. Its assembly and transport depend on the joining chain (J-chain) and the polymeric immunoglobulin receptor (pIgR), but the underlying molecular mechanisms of these processes are unclear. We report a cryo–electron microscopy structure of the Fc region of human IgM in complex with the J-chain and pIgR ectodomain. The IgM-Fc pentamer is formed asymmetrically, resembling a hexagon with a missing triangle. The tailpieces of IgM-Fc pack into an amyloid-like structure to stabilize the pentamer. The J-chain caps the tailpiece assembly and bridges the interaction between IgM-Fc and the polymeric immunoglobulin receptor, which undergoes a large conformational change to engage the IgM-J complex. These results provide a structural basis for the function of IgM.

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Section: Researchmentioning

confidence: 99%

Structural insights into immunoglobulin M

Wang

et al. 2020

Science

100

132

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“…The SC comprises five Ig-like domains, of which D1 is both necessary and sufficient for pIgA binding, whereas D2 to D5 provide affinity enhancement (14,15). Previous structural analysis of the SC showed that in the absence of pIgA, the SC adopts a closed conformation stabilized by the interaction among D1, D4, and D5 (fig.…”

Section: Structure Of the Sc And Interaction With Pigamentioning

confidence: 99%

Structure of the secretory immunoglobulin A core

Kumar¹,

Arthur²,

Ciferri³

et al. 2020

Science

111

115

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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. In recent 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.

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“…This suggests that Ig like domains 2 and 3 may be necessary for maintaining the correct orientation of Ig like domain 5 and allow disulfide bonding with the Ca3 domain of IgA (53-55). On the other hand, Ig like domain 1 of rabbit pIgR was found to bind pIgA with equivalent affinity to the full-length SC, and the deletion of Ig like domains 2 and 3 did not diminish binding to pIgA (56,57). These species-specific differences in pIgA-pIgR interactions may provide a functional explanation for species-specific differences in alternative splicing of the exon encoding Ig like domains 2 and 3 in pIgR mRNA, since both the full-length rabbit pIgR and the alternative-spliced variant lacking the Ig like domains 2 and 3 can bind and lead to transcytosis of IgA dimers in vitro (58,59).…”

Section: Discussionmentioning

confidence: 89%

Evolutionary analyses of polymeric immunoglobulin receptor (pIgR) in the mammals reveals an outstanding mutation rate in the lagomorphs

Neves¹,

Sousa-Pereira²,

Melo‐Ferreira³

et al. 2022

Front. Immunol.

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BackgroundThe transcytosis of polymeric immunoglobulins, IgA and IgM, across the epithelial barrier to the luminal side of mucosal tissues is mediated by the polymeric immunoglobulin receptor (pIgR). At the luminal side the extracellular ligand binding region of pIgR, the secretory component (SC), is cleaved and released bound to dimeric IgA (dIgA), protecting it from proteolytic degradation, or in free form, protecting the mucosa form pathogens attacks. The pIgR was first cloned for rabbit in early 1980’s and since then has been described for all vertebrates, from fish to mammals. The existence of more than one functional pIgR alternative-spliced variant in the European rabbit, the complete pIgR as other mammals and a shorter pIgR lacking two SC exons, raised the question whether other lagomorphs share the same characteristics and how has the PIGR gene evolved in these mammals.ResultsTo investigate these questions, we sequenced expressed pIgR genes for other leporid genus, Lepus spp., and obtained and aligned pIgR sequences from representative species of all mammalian orders. The obtained mammalian phylogeny, as well as the Bayesian inference of evolutionary rates and genetic distances, show that Lagomorpha pIgR is evolving at a higher substitution rate. Codon-based analyses of positive selection show that mammalian pIgR is evolving under strong positive selection, with strong incidence in the domains excised from the rabbit short pIgR isoform. We further confirmed that the hares also express the two rabbit pIgR isoforms.ConclusionsThe Lagomorpha pIgR unique evolutionary pattern may reflect a group specific adaptation. The pIgR evolution may be linked to the unusual expansion of IgA genes observed in lagomorphs, or to neofunctionalization in this group. Further studies are necessary to clarify the driving forces behind the unique lagomorph pIgR evolution.

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The amino-terminal domain of rabbit secretory component is responsible for noncovalent binding to immunoglobulin A dimers.

Cited by 71 publications

References 37 publications

Structural insights into immunoglobulin M

Structural insights into immunoglobulin M

Structure of the secretory immunoglobulin A core

Evolutionary analyses of polymeric immunoglobulin receptor (pIgR) in the mammals reveals an outstanding mutation rate in the lagomorphs

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