Computational analysis of prodomain cysteines in human TGF-β proteins reveals frequent loss of disulfide-dependent regulation in tumors.
Computational analysis of prodomain cysteines in human TGF-β proteins reveals frequent loss of disulfide-dependent regulation in tumors.
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DOI：
10.1093/g3journal/jkac271
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发表时间：
2022-12-01
期刊：
影响因子：
--
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中科院分区：
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人转化生长因子-β（TGF-β）家族的功能多样的成员受到严格调控。TGF-β的调节包括2个二硫键依赖性机制-二聚化和伴侣蛋白结合。参与这些调节机制的特定半胱氨酸仅在33种人TGF-β蛋白中的3种中已知。人前结构域比对显示，24个TGF-β前结构域在2个高度暴露的位置含有保守的半胱氨酸。在β8螺旋的区域中有3个介导前结构域羧基末端附近的二聚化。在缔合区中有2个，其介导伴侣蛋白在前结构域氨基末端附近的结合。比对预测了有助于72%的人TGF-β蛋白的二硫键依赖性调节的特异性半胱氨酸。数据库挖掘，然后确定了9个保守的前结构域半胱氨酸突变及其疾病表型在7个TGF-β蛋白。前结构域半胱氨酸突变的三种常见腺瘤表型表明有7种新的调节异二聚体对。两种常见的腺瘤表型的前结构域和结合伴侣半胱氨酸突变揭示了17个新的监管相互作用。总的来说，人TGF-β前结构域的分析表明，通过异源二聚化和伴侣蛋白结合的二硫键依赖性调节的范围显著扩大;调节通常在肿瘤中丢失。
The functionally diverse members of the human Transforming Growth Factor-β (TGF-β) family are tightly regulated. TGF-β regulation includes 2 disulfide-dependent mechanisms—dimerization and partner protein binding. The specific cysteines participating in these regulatory mechanisms are known in just 3 of the 33 human TGF-β proteins. Human prodomain alignments revealed that 24 TGF-β prodomains contain conserved cysteines in 2 highly exposed locations. There are 3 in the region of the β8 helix that mediates dimerization near the prodomain carboxy terminus. There are 2 in the Association region that mediates partner protein binding near the prodomain amino terminus. The alignments predict the specific cysteines contributing to disulfide-dependent regulation of 72% of human TGF-β proteins. Database mining then identified 9 conserved prodomain cysteine mutations and their disease phenotypes in 7 TGF-β proteins. Three common adenoma phenotypes for prodomain cysteine mutations suggested 7 new regulatory heterodimer pairs. Two common adenoma phenotypes for prodomain and binding partner cysteine mutations revealed 17 new regulatory interactions. Overall, the analysis of human TGF-β prodomains suggests a significantly expanded scope of disulfide-dependent regulation by heterodimerization and partner protein binding; regulation that is often lost in tumors.
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DOI：
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发表时间：
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期刊：
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影响因子：
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