Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT
Selective inhibition of NFAT activation by a peptide spanning the calcineurin targeting site of NFAT
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DOI：
10.1016/s1097-2765(00)80063-5
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发表时间：
1998-04-01
期刊：
影响因子：
16
通讯作者：
Hogan, PG
中科院分区：
文献类型：
--
作者：
Aramburu, J;Garcia-Cozar, F;Hogan, PG
NFAT转录因子在免疫反应中起关键作用。 NFAT蛋白的激活由钙调蛋白（钙调蛋白依赖性磷酸酶抑制，被免疫抑制药物Cyclosporin A和FK506抑制）。在这里，我们确定了NFAT蛋白中的一个短序列，该序列将钙调神经蛋白靶向NFAT。在此序列中，单个残基的突变会损害钙调蛋白介导的去磷酸化和NFAT1的核转运。跨越该区域的肽抑制了钙调神经蛋白与NFAT蛋白结合和去磷酸化的能力，而不会影响钙调蛋白对其他底物的磷酸酶活性。细胞内表达时，相应的肽会抑制NFAT去磷酸化，核转运和NFAT介导的基因表达，以响应刺激。因此，将钙调神经酶引导到NFAT的酶 - 基底对接相互作用可以有效地阻断NFAT依赖性功能。
NFAT transcription factors play a key role in the immune response. The activation of NFAT proteins is controlled by calcineurin, the calmodulin-dependent phosphatase that is inhibited by the immunosuppressive drugs cyclosporin A and FK506. Here, we identify a short conserved sequence in NFAT proteins that targets calcineurin to NFAT. Mutation of a single residue in this sequence impairs the calcineurin-mediated dephosphorylation and nuclear translocation of NFAT1. Peptides spanning the region inhibit the ability of calcineurin to bind to and dephosphorylate NFAT proteins, without affecting the phosphatase activity of calcineurin against other substrates. When expressed intracellularly, a corresponding peptide inhibits NFAT dephosphorylation, nuclear translocation, and NFAT-mediated gene expression in response to stimulation. Thus, disruption of the enzyme-substrate docking interaction that directs calcineurin to NFAT can effectively block NFAT-dependent functions.