FKBP12 binds the inositol 1,4,5-trisphosphate receptor at leucine-proline (1400-1401) and anchors calcineurin to this FK506-like domain
FKBP12 binds the inositol 1,4,5-trisphosphate receptor at leucine-proline (1400-1401) and anchors calcineurin to this FK506-like domain
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DOI：
10.1074/jbc.272.44.27582
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发表时间：
1997-10-31
影响因子：
4.8
通讯作者：
Snyder, SH
中科院分区：
文献类型：
--
作者：
Cameron, AM;Nucifora, FC;Snyder, SH
FKBP 12是生物学中最丰富和保守的蛋白质之一。它是药物FK 506免疫抑制作用的主要受体，在药物FK 506存在时，FKBP 12结合并抑制钙调磷酸酶，破坏淋巴细胞中白细胞介素的形成。FKBP 12的生理功能尚不清楚，尽管该蛋白质已被证明与肌醇1，4，5-三磷酸受体（IP 3R）、兰尼碱受体和1型转化生长因子β受体发生生理相互作用。我们现在报告FKBP 12在残基1400-1401处结合IP 3R，这是一种结构上类似于FK 506的亮氨酰-脯氨酰二肽表位。我们进一步证明，在该位点与IP 3 R的结合使FKBP 12能够与钙调神经磷酸酶相互作用，推测是将磷酸酶锚于IP 3 R并调节受体的磷酸化状态。我们提出，FK 506促进FKBP 12-钙调磷酸酶相互作用的模拟结构相似的二肽表位内的蛋白质，使用FKBP 12锚钙调磷酸酶适当的生理底物。
The immunophilin FKBP12 is one of the most abundant and conserved proteins in biology. It is the primary receptor for the immunosuppressant actions of the drug FK506 in whose presence FKBP12 binds to and inhibits calcineurin, disrupting interleukin formation in lymphocytes. The physiologic functions of FKBP12 are less clear, although the protein has been demonstrated to physiologically interact with the inositol 1,4,5-trisphosphate receptor (IP3R), the ryanodine receptor, and the type 1 transforming growth factor beta receptor. We now report that FKBP12 binds the IP3R at residues 1400-1401, a leucyl-prolyl dipeptide epitope that structurally resembles FK506. We further demonstrate that binding to IP3R at this site enables FKBP12 to interact with calcineurin, presumably to anchor the phosphatase to IP3R and modulate the receptor's phosphorylation status. We propose that FK506 promotes an FKBP12-calcineurin interaction by mimicking structurally similar dipeptide epitopes present within proteins that use FKBP12 to anchor calcineurin to the appropriate physiologic substrates.