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.2023 Oct 23;14(1):6726.
doi: 10.1038/s41467-023-42469-y.

SIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions

Affiliations

SIgA structures bound to Streptococcus pyogenes M4 and human CD89 provide insights into host-pathogen interactions

Qianqiao Liu et al. Nat Commun..

Abstract

Immunoglobulin (Ig) A functions as monomeric IgA in the serum and Secretory (S) IgA in mucosal secretions. Host IgA Fc receptors (FcαRs), including human FcαR1/CD89, mediate IgA effector functions; however, human pathogen Streptococcus pyogenes has evolved surface-protein virulence factors, including M4, that also engage the CD89-binding site on IgA. Despite human mucosa serving as a reservoir for pathogens, SIgA interactions with CD89 and M4 remain poorly understood. Here we report cryo-EM structures of M4-SIgA and CD89-SIgA complexes, which unexpectedly reveal different SIgA-binding stoichiometry for M4 and CD89. Structural data, supporting experiments, and modeling indicate that copies of SIgA bound to S. pyogenes M4 will adopt similar orientations on the bacterium surface and leave one host FcαR binding site open. Results suggest unappreciated functional consequences associated with SIgA binding to host and bacterial FcαRs relevant to understanding host-microbe co-evolution, IgA effector functions and improving the outcomes of group A Streptococcus infection.

© 2023. Springer Nature Limited.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Structures of mIgA, SIgA, and schematic of M4.
a The structure of mIgA lacking Fabs (Fcα; PDB code1OW0 with CD89 removed).b The structure of human SIgA lacking Fabs (PDB code6UE7). Structures are colored according to the key; one Cα2 and one Cα3 domain are labeled along with FcAB and FcCD. The SIgA tailpieces (Tps) are labeled and indicated with a black arrow and the FcαR binding sites are indicated by orange arrows.c Schematic of M4 depicted attached to the GAS cell wall through a C-terminal proline-glycine-threonine-serine (PGTS)-rich domain and a cell-wall-associated domain, which are followed by an ectodomain that includes three C-repeats, an IgA-binding region and an N-terminal hypervariable domain (HVR).
Fig. 2
Fig. 2. SIgA-M4 Structure.
a The Cryo-EM structure of the M4 fragment (residues 45–73) in complex with human SIgA is shown as a cartoon with a partially transparent map in two orientations. The model is colored according to the key, M4 is labeled, and Fabs are disordered.b Sequence alignment of the IgA-binding regions of M4 and M22 with their heptad registrations shown above; numbering corresponds to both sequences, and M4 residues interacting with IgA are depicted in bold.c Cartoon representation showing interchain interactions between M4 helix a and b. Polar interactions are shown as dotted lines.
Fig. 3
Fig. 3. The M4-SIgA interface.
a Structure of the M4-SIgA interface. The boxed regions are enlarged (1–3) and depict the (1) M4 helix-a interaction with HC-A, (2) M4 helix-b interactions with HC-A, and (3) M4 interactions with HC-B. Black dotted lines indicate potential hydrogen bonds.b Polar and hydrophobic interactions between IgA and M4. Asterisks indicate residues contributing to hydrophobic interactions.c M4 binding analysis by surface plasmon resonance (SPR). The sensorgram shows the response of M4 (black) and individual M4 point mutants Q47A (green), R49A (yellow), and K68A (blue) binding to immobilized human SIgA1. All analyte concentrations shown are 0.125 uM. Sensorgrams, including a complete concentration series for each analyte, binding models and rate constants, can be found in Supplementary Fig. 3 and Supplementary Table 2. Source data are provided in the Source Data file.
Fig. 4
Fig. 4. SIgA-CD89 structure.
a The Cryo-EM structure of CD89 in complex with human SIgA is shown as a cartoon with a partially transparent map in two orientations. The antigen-binding fragments (Fabs) are disordered. The two Ig-like domains of CD89 are labeled D1 and D2. CD89 D1 contacted a total of 19 IgA residues, including Cα2 residues L256, L257, L258 and Cα3 residues E348, R382, L384, S387, E389, M433, H436, E437, A438, L439, P440, L441, A442, F443, T444, Q445.b Alignment of the mIgA-CD89 crystal structure (PDB:1OW0) to the FcAB-CD89 interface (left) and FcCD-CD89 interface (right) on SIgA-CD89. The BC, DE and FG loops are labeled on FcAB-CD89.c Crystal structure of CD89 in complex with human Fcα (PDB code:1OW0). All models are colored according to the keys. The C-termini of CD89 D2 domains are indicated by red spheres, which on CD89-SIgA are 108 Å apart.
Fig. 5
Fig. 5. M4 and CD89-binding site comparison and modeling.
a Comparison of M4 and CD89-binding sites on Fcα shown in two orientations. Fcα is shown as ribbons, and binding residues are shown as stick representation. The 11 residues bound by M4 are shown in pink and yellow and the 19 residues bound by CD89 are shown in orange and yellow. In all panels, five shared binding site residues, E389, L441, F443, T444, Q445, are colored yellow.b M4 modeled at the second site (FcCD; blue) is partially overlapping with JC (magenta), indicating a steric clash.c Model of M4 (pink) and CD89 (orange) bound SIgA. CD89 bound to the FcCD site does not clash with SIgA residues.
Fig. 6
Fig. 6. Schematic model of human SIgA binding to M4 on a GAS surface.
a AlphaFold2-multimer predicted M4 dimer; residues 287–316 are predicted to be disordered and not shown. The IgA-binding region on the predicted model is colored in pink and has an RMSD of 0.640 when aligned to the SIgA-M4 structure.b Surface-associated M4, shown in two orientations, binds to one side of SIgA (FcAB), holding all SIgA at a similar orientation and distance from the bacterium surface while leaving the FcCD FcαR binding site (red sphere) open. Possible locations of disordered Fabs are shown as gray and green ovals. CD89 binding to M4-bound SIgA is sterically possible and modeled on one copy of the SIgA-M4 complex. SIgA SC domain D2 is indicated by a circle and is exposed near the outermost surface of the bacterium.
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