Convergent evolution of a parasite-encoded complement control protein-scaffold to mimic binding of mammalian TGF-ß to its receptors, TßRI and TßRII

Mukundan, A., Byeon, C.-H., Hinck, C. S., Cunningham, K., Campion, T., Smyth, D. J. , Maizels, R. M. and Hinck, A. P. (2022) Convergent evolution of a parasite-encoded complement control protein-scaffold to mimic binding of mammalian TGF-ß to its receptors, TßRI and TßRII. Journal of Biological Chemistry, 298(6), 101994. (doi: 10.1016/j.jbc.2022.101994) (PMID:35500648) (PMCID:PMC9163516)

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Abstract

The mouse intestinal helminth Heligmosomoides polygyrus modulates host immune responses by secreting a TGF-β mimic, TGM, to expand the population of Foxp3+ Tregs. TGM comprises five complement control protein (CCP)-like domains, designated D1-D5. Though lacking homology to TGF-β, TGM binds directly to TGF-β receptors TβRI and TβRII and stimulates the differentiation of naïve T-cells into Tregs. However, the molecular determinants of this binding are unclear. Here, we used surface plasmon resonance, isothermal calorimetry, NMR spectroscopy, and mutagenesis to investigate how TGM binds the TGF-β receptors. We demonstrate that binding is modular, with domains D1 and D2 binding to TβRI and D3 binding to TβRII. D1-D2 and D3 were further shown to compete with TGF-β(TβRII)2 and TGF-β for binding to TβRI and TβRII, respectively. The solution structure of TGM-D3 revealed that TGM adopts a CCP-like fold, but also that it is modified to allow the C-terminal strand to diverge, leading to an expansion of the domain and opening potential interaction surfaces. TGM-D3 also incorporates a long structurally ordered hypervariable loop, adding further potential interaction sites. Through NMR shift perturbations and binding studies of TGM-D3 and TβRII variants, TGM-D3 was shown to occupy the same site of TβRII as that bound by TGF-β using both a novel interaction surface and the hypervariable loop. These results, together with the identification of other secreted CCP-like proteins with immunomodulatory activity in H. polygyrus, suggest that TGM is part of a larger family of evolutionarily-plastic parasite effector molecules that mediate novel interactions with their host.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smyth, Dr Danielle and Maizels, Professor Rick and Cunningham, Mr Kyle and Campion, Ms Tiffany
Authors: Mukundan, A., Byeon, C.-H., Hinck, C. S., Cunningham, K., Campion, T., Smyth, D. J., Maizels, R. M., and Hinck, A. P.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Journal of Biological Chemistry
Publisher:Elsevier
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:29 April 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Journal of Biological Chemistry 298(6): 101994
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
308411Molecular and Cellular Interactions in Helminth InfectionsRichard MaizelsWellcome Trust (WELLCOTR)219530/Z/19/ZIII - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology