Protein-protein interactions controlling nitric oxide synthases.
Protein-protein interactions controlling nitric oxide synthases.
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DOI：
10.1046/j.1365-201x.2000.00629.x
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
B. Kone
中科院分区：
文献类型：
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作者：
B. Kone
一氧化氮(NO)的生物合成受到从转录调控到翻译后调控的多种机制的严格调控。钙调蛋白长期以来被认为是三种主要的一氧化氮合酶(NOS)的变构调节剂。最近的研究表明，其他蛋白质直接与一氧化氮合酶亚型结合，调节其活性或在细胞内的空间分布。内皮型一氧化氮合酶(ENOS)的变构调节蛋白存在于内皮细胞的质膜小窝中或聚集到内皮膜小窝中。小窝驻留的支架蛋白Caveolins和钙调蛋白与小窝内eNOS发生相互的钙依赖结合和解离，从而抑制(Caveolin)和激活(CaM)eNOS的活性。其他空泡蛋白似乎对eNOS-膜复合体有贡献，包括缓激素B2受体、血管紧张素AT1受体、CAT1精氨酸转运体和Hsp90。许多含有PDZ结构域的蛋白质与神经元型一氧化氮合酶(NNOS)的PDZ结构域的直接相互作用已被证明影响大脑和肌肉中该酶的亚细胞分布和/或活性。其中一种蛋白质PSD-93与致密黄斑中的nNOS亚群共定位。尽管转录被认为是诱导型一氧化氮合酶(INOS)调控的主要步骤，但我们的实验室最近定义了iNOS与Rho家族GTP酶的调控相互作用。虽然蛋白质-eNOS相互作用在控制血管张力中的作用已经越来越清楚，但蛋白质与nNOS和iNOS在血管和肾脏中的相互作用和调节重要性仍有待探索。
Nitric oxide (NO) biosynthesis is tightly regulated by a variety of mechanisms ranging from transcriptional to post-translational controls. Calmodulin has long been known to be an allosteric modulator of the three major NO synthases (NOS). Recent studies indicate that other proteins directly associate with NOS isoforms and regulate their activity or spatial distribution in the cell. Several proteins residing in or recruited to plasmalemmal caveolae of endothelial cells serve as allosteric regulators of endothelial NOS (eNOS). Caveolins, the resident scaffolding proteins of caveolae, and calmodulin undergo reciprocal Ca2+-dependent association and dissociation with eNOS in the caveolar membrane that inhibits (caveolins) and activates (calmodulin) eNOS activity. Other caveolar proteins appear to contribute to the eNOS-membrane complex, including the bradykinin B2 receptor, the angiotensin AT1 receptor, the CAT1 arginine transporter, and Hsp90. Direct interactions of a variety of proteins bearing PDZ domains with the PDZ domain of neuronal NOS (nNOS) have been shown to influence the subcellular distribution and/or activity of the enzyme in brain and muscle. One of these proteins, PSD-93, co-localizes with a subpopulation of nNOS in the macula densa. Although considerable emphasis has been placed on transcription as the principal step of regulation for inducible NOS (iNOS), our laboratory has recently defined a regulatory interaction of iNOS with Rho family GTPases. While the role of protein-eNOS interactions in the control of vascular tone has been increasingly clarified, the interactions and regulatory importance of protein association with nNOS and iNOS in the vasculature and kidney remains to be explored.