Smad7 Inhibits Transforming Growth Factor-β Family Type I Receptors through Two Distinct Modes of Interaction
Smad7 Inhibits Transforming Growth Factor-β Family Type I Receptors through Two Distinct Modes of Interaction
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DOI：
10.1074/jbc.m110.166140
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发表时间：
2010-10-01
影响因子：
4.8
通讯作者：
Miyazawa, Keiji
中科院分区：
文献类型：
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作者：
Kamiya, Yuto;Miyazono, Kohei;Miyazawa, Keiji
抑制性Smads（I-Smads），即Smad 6和Smad 7，是转化生长因子-β（TGF-β）家族信号传导的负调节剂。I-Smads主要通过与I型受体（激活素受体样激酶）的物理相互作用来抑制TGF-β家族信号传导，从而与受体调节的Smads（R-Smads）竞争激活。然而，I-Smads如何与I型受体相互作用尚不清楚。在本研究中，我们发现Smad 7与I型受体有两种相互作用模式。一种是通过MH 2结构域中的三指状结构，由残基331-361、379-387和L3环组成。另一种是通过MH 2结构域中的碱性沟（Mochizuki，T.，宫崎，H.，Hara，T.，Furuya，T.，Imamura，T.，Watabe，T.，Miyazono，K.（2004）J.Biol.Chem.279，31568-31574）。我们还发现Smad 6主要利用MH 2结构域中的碱性沟与I型受体相互作用。因此，Smad 7具有与TGF-β家族I型受体相互作用的额外模式，而Smad 6不具有这种相互作用，这可能在介导Smad 7特有的抑制作用中发挥作用。
The inhibitory Smads (I-Smads), i.e. Smad6 and Smad7, are negative regulators of transforming growth factor-beta (TGF-beta) family signaling. I-Smads inhibit TGF-beta family signaling principally through physical interaction with type I receptors (activin receptor-like kinases), so as to compete with receptor-regulated Smads (R-Smads) for activation. However, how I-Smads interact with type I receptors is not well understood. In the present study, we found that Smad7 has two modes of interaction with type I receptors. One is through a three-finger-like structure in the MH2 domain, consisting of residues 331-361, 379-387, and the L3 loop. The other is through a basic groove in the MH2 domain (Mochizuki, T., Miyazaki, H., Hara, T., Furuya, T., Imamura, T., Watabe, T., and Miyazono, K. (2004) J. Biol. Chem. 279, 31568-31574). We also found that Smad6 principally utilizes a basic groove in the MH2 domain for interaction with type I receptors. Smad7 thus has an additional mode of interaction with TGF-beta family type I receptors not possessed by Smad6, which may play roles in mediating the inhibitory effects unique to Smad7.