Novel insights into the regulation of malarial calcium-dependent protein kinase 1
Novel insights into the regulation of malarial calcium-dependent protein kinase 1
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DOI：
10.1096/fj.12-203877
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发表时间：
2012-08-01
期刊：
影响因子：
4.8
通讯作者：
Sharma, Pushkar
中科院分区：
文献类型：
--
作者：
Ahmed, Anwar;Gaadhe, Kavita;Sharma, Pushkar
钙依赖蛋白激酶(CDPKs)是弓形虫和疟原虫等顶端复合体寄生虫中钙信号的主要效应者，控制着寄生虫生命周期的重要过程。尽管最近报道了弓形虫CDPKs的晶体结构，但有关其调控的几个重要问题仍未得到解答。恶性疟原虫(PF)CDPK1可能参与宿主细胞的入侵，是疟疾寄生虫生命周期中的关键分子。PfCDPK1的分子模拟和定点突变研究表明，调节域中的几个残基起着双重作用，因为它们似乎有助于活性和非活性激酶的稳定。质谱仪显示，PfCDPK1在几个位置被自动磷酸化；其中一些被放置在战略位置，因此被发现对激酶激活至关重要。PfCDPK1的N端延伸对PfCDPK1的激活是重要的。出乎意料的是，在PfCDPK1的NTE中发现了一个ATP结合位点。我们的研究突出了PfCDPK1调控的几个新特征，这些特征可能与CDPK家族的其他成员相同。-Ahmed，A.，Gaadhe，K.，Sharma，G.P.，Kumar，N.，Neculai，M.，Hue，R.，Mohanty，D.，Sharma，P.对疟疾钙依赖蛋白激酶1调控的新见解。Www.fasebj.org
Calcium-dependent protein kinases (CDPKs) are major effectors of calcium signaling in apicomplexan parasites like Toxoplasma and Plasmodium and control important processes of the parasite life cycle. Despite recently reported crystal structures of Toxoplasma gondii (Tg)CDPKs, several important questions about their regulation remain unanswered. Plasmodium falciparum (Pf)CDPK1 has emerged as a key player in the life cycle of the malaria parasite, as it may be involved in the invasion of the host cells. Molecular modeling and site-directed mutagenesis studies on PfCDPK1 suggested that several residues in the regulatory domain play a dual role, as they seem to contribute to the stabilization of both the active and inactive kinase. Mass spectrometry revealed that PfCDPK1 was autophosphorylated at several sites; some of these were placed at strategic locations and therefore were found to be critical for kinase activation. The N-terminal extension of PfCDPK1 was found to be important for PfCDPK1 activation. Unexpectedly, an ATP binding site in the NTE of PfCDPK1 was identified. Our studies highlight several novel features of PfCDPK1 regulation, which may be shared by other members of the CDPK family. These findings may also aid design of inhibitors against these important targets, which are absent from the host.-Ahmed, A., Gaadhe, K., Sharma, G. P., Kumar, N., Neculai, M., Hui, R., Mohanty, D., Sharma, P. Novel insights into the regulation of malarial calcium-dependent protein kinase 1. FASEB J. 26, 3212-3221 (2012). www.fasebj.org