Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum
Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum
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DOI：
10.1038/ncomms1558
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发表时间：
2011-11-01
影响因子：
16.6
通讯作者：
Doerig, Christian
中科院分区：
文献类型：
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作者：
Solyakov, Lev;Halbert, Jean;Doerig, Christian
蛋白质磷酸化在疟疾寄生虫生命周期中的作用正在慢慢显现。在这里，我们将全局磷酸化蛋白质组分析与全激酶组反向遗传学相结合，以评估蛋白质磷酸化在恶性疟原虫无性增殖中的重要性。我们在 650 种寄生虫蛋白上鉴定出 1177 个磷酸化位点，这些蛋白参与广泛的一般细胞活动，如 DNA 合成、转录和代谢，以及关键的寄生虫过程，如入侵和细胞粘附。几种寄生虫蛋白激酶本身在假定的调节残基上被磷酸化，包括 PfGSK3 和 PfCLK3 激活环中的酪氨酸；我们表明 PfCLK3 Y526 的磷酸化对于完整的激酶活性至关重要。全激酶组反向遗传学策略确定了 36 种寄生虫激酶可能对红细胞分裂至关重要。这些研究不仅揭示了蛋白质磷酸化调节的过程，而且还确定了寄生虫激酶组内潜在的抗疟疾药物靶点。
The role of protein phosphorylation in the life cycle of malaria parasites is slowly emerging. Here we combine global phospho-proteomic analysis with kinome-wide reverse genetics to assess the importance of protein phosphorylation in Plasmodium falciparum asexual proliferation. We identify 1177 phosphorylation sites on 650 parasite proteins that are involved in a wide range of general cellular activities such as DNA synthesis, transcription and metabolism as well as key parasite processes such as invasion and cyto-adherence. Several parasite protein kinases are themselves phosphorylated on putative regulatory residues, including tyrosines in the activation loop of PfGSK3 and PfCLK3; we show that phosphorylation of PfCLK3 Y526 is essential for full kinase activity. A kinome-wide reverse genetics strategy identified 36 parasite kinases as likely essential for erythrocytic schizogony. These studies not only reveal processes that are regulated by protein phosphorylation, but also define potential anti-malarial drug targets within the parasite kinome.