Convergent evolution of a parasite-encoded complement control protein-scaffold to mimic binding of mammalian TGF-β to its receptors, TβRI and TβRII

Ananya Mukundan, Chang Hyeock Byeon, Cynthia S. Hinck, Kyle Cunningham, Tiffany Campion, Danielle J. Smyth, Rick M. Maizels, Andrew P. Hinck

Research output: Contribution to journalArticlepeer-review

Abstract

The mouse intestinal helminth Heligmosomoides polygyrus modulates host immune responses by secreting a transforming growth factor (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 the TGF-β receptors TβRI and TβRII and stimulates the differentiation of naïve T-cells into Tregs. However, the molecular determinants of 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 D1-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 is also 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 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.

Original languageEnglish (US)
Article number101994
JournalJournal of Biological Chemistry
Volume298
Issue number6
DOIs
StatePublished - Jun 2022
Externally publishedYes

Keywords

  • H.polygyrus
  • immune suppression
  • isothermal titration calorimetry
  • nuclear magnetic resonance
  • parasite
  • regulatory T cell
  • surface plasmon resonance
  • TGF-β
  • TGF-β mimic
  • TGM

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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