Convergent evolution of a parasite-encoded complement control protein-scaffold to mimic binding of mammalian TGF-β to its receptors, TβRI and TβRII.
Convergent evolution of a parasite-encoded complement control protein-scaffold to mimic binding of mammalian TGF-β to its receptors, TβRI and TβRII.
复制标题
DOI：
10.1016/j.jbc.2022.101994
复制
发表时间：
2022-06
影响因子：
4.8
通讯作者：
Hinck, Andrew P.
中科院分区：
文献类型：
--
作者：
Mukundan, Ananya;Byeon, Chang-Hyeock;Hinck, Cynthia S.;Cunningham, Kyle;Campion, Tiffany;Smyth, Danielle J.;Maizels, Rick M.;Hinck, Andrew P.
小鼠肠道蠕虫Heligmosomoides polygyrus通过分泌转化生长因子（TGF）-β模拟物（TGM）来调节宿主免疫应答，以扩大Foxp 3 + TGM的群体。TGM包含五个补体控制蛋白（CCP）样结构域，命名为D1-D5。尽管TGM与TGF-β缺乏同源性，但它直接与TGF-β受体TβRI和TβRII结合，并刺激幼稚T细胞分化为TGM。然而，结合的分子决定因素尚不清楚。在这里，我们使用表面等离子体共振，等温量热法，NMR光谱和诱变来研究TGM如何结合TGF-β受体。我们证明了结合是模块化的，D1-D2结合TβRI，D3结合TβRII。进一步显示D1-D2和D3分别与TGF-β（TβRII）2和TGF-β竞争结合TβRI和TβRII。TGM-D3的溶液结构显示，TGM采用CCP样折叠，但也被修饰以允许C-末端链分叉，导致结构域扩展并打开潜在的相互作用表面。TGM-D3还包含一个长的结构有序的高变环，增加了进一步的潜在相互作用位点。通过对TGM-D3和TβRII变体的NMR位移扰动和结合研究，使用新的相互作用表面和高变环，显示TGM-D3占据与TGF-β结合的TβRII相同的位点。这些结果，以及其他分泌的CCP样蛋白的鉴定与免疫调节活性的H. polygyrus，表明TGM是一个更大的家族的进化塑料寄生虫效应分子介导的新的相互作用与他们的主机的一部分。
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.
登录
查看更多内容
DOI：
10.1084/jem.20101074
发表时间：
2010-10-25
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Grainger JR;Smith KA;Hewitson JP;McSorley HJ;Harcus Y;Filbey KJ;Finney CA;Greenwood EJ;Knox DP;Wilson MS;Belkaid Y;Rudensky AY;Maizels RM
通讯作者：
Maizels RM
影响因子：
2.7
作者：
Hinck, AP;Walker, KP;Freedberg, DI
通讯作者：
Freedberg, DI
影响因子：
2.7
作者：
Ilangovan, U;Deep, S;Hinck, AP
通讯作者：
Hinck, AP
影响因子：
6.7
作者：
Hewitson, James P.;Ivens, Al C.;Maizels, Rick M.
通讯作者：
Maizels, Rick M.
影响因子：
2.7
作者：
DELAGLIO, F;GRZESIEK, S;BAX, A
通讯作者：
BAX, A