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Publication Abstract from PubMed

The mouse intestinal helminth Heligmosomoides polygyrus modulates host immune responses by secreting a TGF-beta 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-beta, TGM binds directly to TGF-beta receptors TbetaRI and TbetaRII and stimulates the differentiation of naive 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-beta receptors. We demonstrate that binding is modular, with domains D1 and D2 binding to TbetaRI and D3 binding to TbetaRII. D1-D2 and D3 were further shown to compete with TGF-beta(TbetaRII)2 and TGF-beta for binding to TbetaRI and TbetaRII, 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 TbetaRII variants, TGM-D3 was shown to occupy the same site of TbetaRII as that bound by TGF-beta 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.

Convergent evolution of a parasite-encoded complement control protein-scaffold to mimic binding of mammalian TGF-beta to its receptors, TbetaRI and TbetaRII.,Mukundan A, Byeon CH, Hinck CS, Cunningham K, Campion T, Smyth DJ, Maizels RM, Hinck AP J Biol Chem. 2022 Apr 29:101994. doi: 10.1016/j.jbc.2022.101994. PMID:35500648^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.