The Nonplanar Secretory IgA2 and Near Planar Secretory IgA1 Solution Structures Rationalize Their Different Mucosal Immune Responses

Abstract

Secretory IgA (SIgA) is the most prevalent human antibody and is central to mucosal immunity. It exists as two subclasses, SIgA1 and SIgA2, where SIgA2 has a shorter hinge joining the Fab and Fc regions. Both forms of SIgA are predominantly dimeric and contain an additional protein called the secretory component (SC) that is attached during the secretory process and is believed to protect SIgA in harsh mucosal conditions. Here we locate the five SC domains relative to dimeric IgA2 within SIgA2 using constrained scattering modeling. The x-ray and sedimentation parameters showed that SIgA2 has an extended solution structure. The constrained modeling of SIgA2 was initiated using two IgA2 monomers that were positioned according to our best fit solution structure for dimeric IgA1. SC was best located along the convex edge of the Fc-Fc region. The best fit models showed that SIgA2 is significantly nonplanar in its structure, in distinction to our previous near planar SIgA1 structure. Both the shorter IgA2 hinges and the presence of SC appear to displace the four Fab regions out of the Fc plane in SIgA2. This may explain the noncovalent binding of SC in some SIgA2 molecules. This nonplanar structure is predicted to result in specific immune properties for SIgA2 and SIgA1. It may explain differences observed between the SIgA1 and SIgA2 subclasses in terms of their interactions with antigens, susceptibility to proteases, effects on receptors, and distribution in different tissues. The different structures account for the prevalence of both forms in mucosal secretions.

C-reactive Protein Exists in an NaCl Concentration-dependent Pentamer-Decamer Equilibrium in Physiological Buffer

“…CRP normally circulates in blood at a median value of 0.0008 mg/ml, which can be as low as 50 ng/ml, but this increases to over 0.5 mg/ml following an acute phase stimulus (a range of 0.4 nM to 4.4 M) (1). Using previously established methods (29,30), we show from AUC size distribution analyses c(s) that pentamers and decamers of CRP are readily identified, whereas constrained x-ray scattering modeling quantified the amounts of pentamers and decamers in solution. We show that SPR observes a similar degree of CRP self-association with immobilized CRP at surfaces in 140 mM NaCl (31).…”

Translocalized IgA mediates neutralization and stimulates innate immunity inside infected cells

“…In fluorescence titration experiments, an increase in anisotropy was observed on addition of S-IgA to TRIM21 PRYSPRY, but a sufficiently high concentration of antibody could not be reached to determine affinity ( serum IgA data suggests that the presence of the SC is inhibitory to TRIM21 binding of IgA. The association of SC with IgA is dependent on disulphide bridges: both because of a direct covalent bond with C α 2 and indirectly because the J-chain is required and it also forms disulphide bridges, with a cysteine at the end of C α 3 (16). Given that the cytosol of the cell is reducing, unlike endocytic compartments or the extracellular environment, we hypothesized that perhaps the J chain and SC detach from S-IgA when it is brought into the cytosol by virus.…”

“…Of these, one neutralized infection independently of TRIM21, whereas in the other, depletion of TRIM21 partially rescued infection. The ability of TRIM21 to use S-IgA was surprising given that the SC binding site overlaps TRIM21 (15), although the SC is not thought to engage both heavy chains in each IgA monomer (16). In fluorescence titration experiments, an increase in anisotropy was observed on addition of S-IgA to TRIM21 PRYSPRY, but a sufficiently high concentration of antibody could not be reached to determine affinity ( serum IgA data suggests that the presence of the SC is inhibitory to TRIM21 binding of IgA.…”

Are anti-HIV IgAs good guys or bad guys?

“…As a consequence of their open hinge region, IgA1 molecules have a T-like shape, in which the distance between Fab fragments measures approximately 16 nm [6][7][8]. In contrast, IgA2 is Y-shaped, and the distance between Fab regions is only 10 nm due to the shorter and stiffer hinge region [7][8][9]. The structural differences between IgA1 and IgA2 molecules are likely associated with differential biological activities.…”