Self-association of Calcium-binding Protein S100A4 and Metastasis
Self-association of Calcium-binding Protein S100A4 and Metastasis
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DOI：
10.1074/jbc.m109.010892
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发表时间：
2010-01-08
影响因子：
4.8
通讯作者：
Barraclough, Roger
中科院分区：
文献类型：
--
作者：
Ismail, Thamir M.;Zhang, Shu;Barraclough, Roger
钙结合蛋白S100A4的水平升高促进转移，癌细胞中的钙结合蛋白S100A4水平升高与癌症患者的生存率降低有关。S100A4与靶蛋白相互作用，影响与转移细胞相关的许多活动。然而，目前还不清楚S100A4促进的转移需要多少这些相互作用，从而阻碍了S100A4诱导转移的特异性抑制剂的设计。在细胞内，S100A4以同源二聚体的形式存在，通过先前发现的、保守的、主要是疏水性的亚基之间的关键接触。研究表明，仅将关键残基苯丙氨酸72突变为丙氨酸就足以将S100A4的促转移活性降低到野生型蛋白的50%，而仅有2到3个特定突变就足以使S100A4的促转移活性降低到野生型蛋白的20%以下。这些突变抑制了S100A4在体内的自结合，并显著降低了S100A4对至少两个蛋白质靶标--非肌肉肌球蛋白重链异构体A的重组片段和P53的亲和力。抑制S100蛋白的自结合可能是抑制其促转移活性的一种新方法。
Elevated levels of the calcium-binding protein S100A4 promote metastasis and in carcinoma cells are associated with reduced survival of cancer patients. S100A4 interacts with target proteins that affect a number of activities associated with metastatic cells. However, it is not known how many of these interactions are required for S100A4-promoted metastasis, thus hampering the design of specific inhibitors of S100A4-induced metastasis. Intracellular S100A4 exists as a homodimer through previously identified, well conserved, predominantly hydrophobic key contacts between the sub-units. Here it is shown that mutating just one key residue, phenylalanine 72, to alanine is sufficient to reduce the metastasis-promoting activity of S100A4 to 50% that of the wild type protein, and just 2 or 3 specific mutations reduces the metastasis-promoting activity of S100A4 to less than 20% that of the wild type protein. These mutations inhibit the self-association of S100A4 in vivo and reduce markedly the affinity of S100A4 for at least two of its protein targets, a recombinant fragment of non-muscle myosin heavy chain isoform A, and p53. Inhibition of the self-association of S100 proteins might be a novel means of inhibiting their metastasis-promoting activities.