The L3 loop:: a structural motif determining specific interactions between SMAD proteins and TGF-β receptors
The L3 loop:: a structural motif determining specific interactions between SMAD proteins and TGF-β receptors
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DOI：
10.1093/emboj/17.4.996
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发表时间：
1998-02-16
期刊：
影响因子：
11.4
通讯作者：
Massagué, J
中科院分区：
文献类型：
--
作者：
Lo, RS;Chen, YG;Massagué, J
转化生长因子β的信号转导特异性（TGF-β）系统由受体复合物的配体活化决定，受体复合物然后募集并磷酸化SMAD蛋白的子集，包括Smads 1和2。然后这些SMAD蛋白与Smad 4缔合并移动到细胞核中，在那里它们调节转录，我们已经确定了一个离散的表面结构在Smads 1和2介导和指定他们的受体相互作用，这个结构是L3环。L3环序列在TGF-β和骨形态发生蛋白（BMP）激活的SMADS中是不变的，但在这两组之间有两个位置不同。在Smads 1和2中交换这两个氨基酸分别诱导获得或损失，它们与TGF-β受体复合物结合并分别引起BMP和TGF-β受体对Smads 1和2的磷酸化的转换的能力，Smads 1和2的磷酸化和活化的完全转换通过交换这两个氨基酸和C-末端受体磷酸化位点附近的四个氨基酸获得，这些研究确定了L3环作为特定SMAD-受体相互作用的决定因素，并表明L3环与C-末端尾一起指定SMAD激活。
Signal transduction specificity in the transforming growth factor-beta (TGF-beta) system is determined by ligand activation of a receptor complex which then recruits and phosphorylates a subset of SMAD proteins including Smads 1 and 2, These then associate with Smad4 and move into the nucleus where they regulate transcription, We have identified a discrete surface structure in Smads 1 and 2 that mediates and specifies their receptor interactions, This structure is the L3 loop. a 17 amino acid region that protrudes from the core of the conserved SMAD C-terminal domain, The L3 loop sequence is invariant among TGF-beta- and bone morphogenetic protein (BMP)-activated SMADS, but differs at two positions between these two groups, Swapping these two amino acids in Smads 1 and 2 induces a gain or loss, respectively, in their ability to associate with the TGF-beta receptor complex and causes a switch in the phosphorylation of Smads 1 and 2 by the BMP and TGF-beta receptors, respectively, A full switch in phosphorylation and activation of Smads 1 and 2 is obtained by swapping both these two amino acids and four amino acids near the C-terminal receptor phosphorylation sites, These studies identify the L3 loop as a determinant of specific SMAD-receptor interactions, and indicate that the L3 loop, together with the C-terminal tail, specifies SMAD activation.