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The structures of secretory and dimeric immunoglobulin A

Kumar Bharathkar, Sonya and Parker, Benjamin W. and Malyutin, Andrey G. and Haloi, Nandan and Huey-Tubman, Kathryn E. and Tajkhorshid, Emad and Stadtmueller, Beth M. (2020) The structures of secretory and dimeric immunoglobulin A. eLife, 2020 (9). Art. No. e56098. ISSN 2050-084X. PMCID PMC7707832. https://resolver.caltech.edu/CaltechAUTHORS:20200218-105856938

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Abstract

Secretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody, which binds pathogens and commensal microbes. SIgA is a polymeric antibody, typically containing two copies of IgA that assemble with one joining-chain (JC) to form dimeric (d) IgA that is bound by the polymeric Ig-receptor ectodomain, called secretory component (SC). Here, we report the cryo-electron microscopy structures of murine SIgA and dIgA. Structures reveal two IgAs conjoined through four heavy-chain tailpieces and the JC that together form a β-sandwich-like fold. The two IgAs are bent and tilted with respect to each other, forming distinct concave and convex surfaces. In SIgA, SC is bound to one face, asymmetrically contacting both IgAs and JC. The bent and tilted arrangement of complex components limits the possible positions of both sets of antigen-binding fragments (Fabs) and preserves steric accessibility to receptor-binding sites, likely influencing antigen binding and effector functions.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.7554/eLife.56098DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707832/PubMed CentralArticle
https://doi.org/10.1101/2020.02.16.951780DOIDiscussion Paper
ORCID:
AuthorORCID
Kumar Bharathkar, Sonya0000-0002-3637-4990
Malyutin, Andrey G.0000-0003-1716-5437
Huey-Tubman, Kathryn E.0000-0002-4683-8138
Tajkhorshid, Emad0000-0001-8434-1010
Additional Information:© 2020, Kumar Bharathkar et al. This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited. Received: 17 February 2020; Accepted: 26 October 2020; Published: 27 October 2020. We thank Pamela Bjorkman and members of the Bjorkman lab at Caltech for supporting preliminary work related to this study as well as Jost Vielmetter and the Caltech Protein Expression Center (housed and funded in part by the Caltech Beckman Institute) for guidance on IgA protein expression strategies. We also thank members of the Stadtmueller Laboratory, as well as Emma Slack (ETH Zurich), for insightful conversations regarding the SIgA and dIgA structures. Cryo Electron microscopy was done in the Beckman Institute cryo-EM resource center at Caltech. The STA121 antibody sequence was provided by Luca Piccoli and the Institute for Research in Biomedicine (Bellinzona, Switzerland). This study was funded by University of Illinois Urbana-Champaign start-up funding, National Institutes Health (United States) grant P41-GM10460, and National Institutes Health (United States) grant R01 AI041239. Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. Molecular graphics and analyses performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Data availability: SIgA and dIgA cryoEM maps and structure coordinate files have been deposited in the EM databank with accession codes EMD-22309 (dIgA) and EMD-22310 (SIgA) and the protein databank with accession codes 7JG1(dIgA) and 7JG2 (SIgA). Author contributions: Sonya Kumar Bharathkar, Benjamin W Parker, Conceptualization, Resources, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing; Andrey G Malyutin, Validation, Investigation, Visualization, Writing - original draft; Nandan Haloi, Formal analysis, Visualization, Methodology, Writing - original draft; Kathryn E Huey-Tubman, Resources, Methodology, Writing - review and editing; Emad Tajkhorshid, Supervision, Funding acquisition, Methodology; Beth M Stadtmueller, Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Writing - original draft, Project administration, Writing - review and editing. The authors declare that no competing interests exist.
Funders:
Funding AgencyGrant Number
University of Illinois Urbana-ChampaignUNSPECIFIED
NIHP41-GM10460
NIHR01 AI041239
NIHP41-GM103311
NIHR01-GM129325
Caltech Beckman InstituteUNSPECIFIED
Issue or Number:9
PubMed Central ID:PMC7707832
Record Number:CaltechAUTHORS:20200218-105856938
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200218-105856938
Official Citation:The structures of Secretory and dimeric Immunoglobulin A. eLife 2020;9: e56098 DOI: 10.7554/eLife.56098
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101321
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:18 Feb 2020 20:07
Last Modified:02 Feb 2021 19:25

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