Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life
Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life
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DOI：
10.1042/bj20030267
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发表时间：
2003-09-01
影响因子：
4.1
通讯作者：
Pérez-Riba, M
中科院分区：
文献类型：
--
作者：
Genescà, L;Aubareda, A;Pérez-Riba, M
钙加压素1是钙调磷酸酶的内源性抑制剂，钙调磷酸酶是在Ca 2+和钙调蛋白控制下的丝氨酸/苏氨酸磷酸酶。钙加压素I由DSCR 1编码，DSCR 1是人类21号染色体上的一个基因，具有7个外显子，外显子1-4是交替的第一外显子（异构体1-4）。我们发现，钙加压素I亚型I的N-末端编码区比以前描述的更长，这产生了一个新的252个氨基酸的多肽。该多肽能够与钙调磷酸酶A相互作用并抑制NF-κ B介导的转录激活。我们首次证明了内源性钙加压素I与钙调神经磷酸酶A和B异源二聚体一起作为复合物存在。钙加压素I是一种磷蛋白，当在FLISPP基序处磷酸化时，其增加抑制钙调磷酸酶的能力，并且这种磷酸化还通过加速其降解来控制钙加压素I的半衰期。此外，我们还检测到FLISPP基序以外的其他磷酸化位点，这些位点有助于钙加压素1的复杂磷酸化模式。考虑到所有这些结果，我们认为钙加压素I的磷酸化参与钙调神经磷酸酶活性的调节，因此可以作为钙调神经磷酸酶依赖性细胞途径的调节剂。
Calcipressin 1 is an endogenous inhibitor of calcineurin, which is a serine/threonine phosphatase under the control of Ca2+ and calmodulin. Calcipressin I is encoded by DSCR1, a gene on human chromosome 21 with seven exons, exons 1-4 are alternative first exons (isoforms 1-4). We show that calcipressin I isoform I has an N-terminal coding region longer than that previously described, and this generates a new polypeptide of 252 amino acids. This polypeptide is able to interact with calcineurin A and to inhibit NF-AT-nnediated transcriptional activation. We demonstrate for the first time that endogenous calcipressin I exists as a complex together with the calcineurin A and B heterodimer. Calcipressin I is a phosphoprotein that increases its capacity to inhibit calcineurin when phosphorylated at the FLISPP motif, and this phosphorylation also controls the half-life of calcipressin I by accelerating its degradation. Additionally, we have also detected further phosphorylation sites outside the FLISPP motif and these contribute to the complex phosphorylation pattern of calcipressin 1. Taking all these results into consideration we suggest that phosphorylation of calcipressin I is involved in the regulation of the phosphatase activity of calcineurin and can therefore act as a modulator of calcineurin-dependent cellular pathways.