In vivo degradation of nitric oxide synthase (NOS) and heat shock protein 90 (HSP90) by calpain is modulated by the formation of a NOS-HSP90 heterocomplex
In vivo degradation of nitric oxide synthase (NOS) and heat shock protein 90 (HSP90) by calpain is modulated by the formation of a NOS-HSP90 heterocomplex
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DOI：
10.1111/j.1742-4658.2008.06394.x
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发表时间：
2008-05-01
期刊：
影响因子：
5.4
通讯作者：
Melloni, Edon
中科院分区：
文献类型：
--
作者：
Averna, Monica;Stifanese, Roberto;Melloni, Edon
我们以前已经表明，孤立的热休克蛋白90（HSP 90）和一氧化氮合酶（NOS），一旦在一个异源复合物，成为完全抵抗钙蛋白酶消化。在这项研究中，它表明，在体内，在钙蛋白酶激活的条件下，发生NOS降解的保护。此外，NOS降解的程度是HSP 90表达水平的函数。因此，在含有大量过量HSP 90的大鼠脑中，几乎所有神经元NOS都与伴侣蛋白相关。在这种情况下，神经元NOS保留其全部催化活性，虽然有限的蛋白水解转化仍然活跃的低分子量（130 kDa）的产品发生。相反，在主动脉中，其中含有少量的HSP 90，内皮NOS是不完全相关的伴侣，并经历了广泛的降解与蛋白质和催化活性的损失。在这些研究结果的基础上，我们提出了一个新的作用的HSP 90-NOS heterocomplex在保护体内的NOS从钙蛋白酶的蛋白水解降解。这种作用的效率与细胞内HSP 90表达水平直接相关，产生高的HSP 90与NOS的比率，这有利于HSP 90-NOS异源复合物的形成和稳定。这种情况似乎发生在大鼠大脑中，但不是在主动脉，从而解释了更高的脆弱性，相对于神经元NOS的内皮NOS的蛋白水解降解。
We have shown previously that isolated heat shock protein 90 (HSP90) and nitric oxide synthase (NOS), once associated in a heterocomplex, become completely resistant to calpain digestion. In this study, it is shown that, in vivo, under conditions of calpain activation, the protection of NOS degradation occurs. In addition, the extent of NOS degradation is a function of the level of HSP90 expression. Thus, in rat brain, which contains a large excess of HSP90, almost all neuronal NOS is associated with the chaperone protein. In this condition, neuronal NOS retains its full catalytic activity, although limited proteolytic conversion to still active low-molecular-mass (130 kDa) products takes place. In contrast, in aorta, which contains much smaller amounts of HSP90, endothelial NOS is not completely associated with the chaperone, and undergoes extensive degradation with a loss of protein and catalytic activity. On the basis of these findings, we propose a novel role of the HSP90-NOS heterocomplex in protecting in vivo NOS from proteolytic degradation by calpain. The efficiency of this effect is directly related to the level of intracellular HSP90 expression, generating a high HSP90 to NOS ratio, which favours both the formation and stabilization of the HSP90-NOS heterocomplex. This condition seems to occur in rat brain, but not in aorta, thus explaining the higher vulnerability to proteolytic degradation of endothelial NOS relative to neuronal NOS.