Evolutionary trace analysis of TGF-β and related growth factors:: implications for site-directed mutagenesis
Evolutionary trace analysis of TGF-β and related growth factors:: implications for site-directed mutagenesis
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DOI：
10.1093/protein/13.12.839
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发表时间：
2000-12-01
期刊：
影响因子：
--
通讯作者：
Blundell, TL
中科院分区：
文献类型：
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作者：
Innis, CA;Shi, JY;Blundell, TL
生长因子家族含有大量的同源蛋白，根据序列同源性分为几个亚家族，这些亚类可以结合成三个更广泛的相关细胞因子组，它们的细胞受体具有明显的特异性：转化生长因子-β、激活素和BMPs/GDF。尽管对于转化生长因子-β家族的一些成员的结构信息是可用的，但关于这些生长因子如何与其多个细胞表面受体的胞外区域或被认为调节其活性的特定蛋白抑制剂相互作用的方式知之甚少，在本文中，我们使用进化跟踪方法[Lichtarge et at(1996)J.Mol]。[生物，257,342-358]为了定位转化生长因子-β样生长因子表面的两个功能斑块，第一个功能斑块集中在一个保守的脯氨酸(在转化生长因子-β1-3中为P-36)，并含有两个氨基酸，可解释转化生长因子-β受体的特异性(H-34和E-35)。第二个补丁位于生长因子前体的另一侧，围绕着一个疏水空腔，其大小足以容纳芳香族残基的侧链。除了第30和32位两个保守的色氨酸外，这个潜在结合界面的主要主角在第31、92、93和98位，几项突变研究强调了生长因子分子的C-末端区域和激活素A中相当于31和94位的激活素A残基对IT型受体与这些配体结合的重要性，这些数据，加上我们对可能功能残基的改进知识，可以用于未来的结构功能分析实验。
The TGF-P family of growth factors contains a large number of homologous proteins, grouped in several subfamilies on the basis of sequence identity, These subgroups can be combined into three broader groups of related cytokines, with marked specificities for their cellular receptors: the TGF-betas, the activins and the BMPs/GDFs. Although structural information is available for some members of the TGF-beta family, very little is known about the way in which these growth factors interact with the extra-cellular domains of their multiple cell surface receptors or with the specific protein inhibitors thought to modulate their activity, In this paper, we use the evolutionary trace method [Lichtarge et at (1996) J.Mol. Biol., 257, 342-358] to locate two functional patches on the surface of TGF-beta -like growth factors, The first of these is centred on a conserved proline (P-36 in TGF-betas 1-3) and contains two amino acids which could account for the receptor specificity of TGF-betas (H-34 and E-35). The second patch is located on the other side of the growth factor protomer and surrounds a hydrophobic cavity, large enough to accommodate the side chain of an aromatic residue. In addition to two conserved tryptophans at positions 30 and 32, the main protagonists in this potential binding interface are found at positions 31, 92, 93 and 98, Several mutagenesis studies have highlighted the importance of the C-terminal region of the growth factor molecule in TGF-betas and of residues in activin A equivalent to positions 31 and 94 of the TGF-betas for the binding of type IT receptors to these ligands, These data, together with our improved knowledge of possible functional residues, can be used in future structure-function analysis experiments.