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Nature:刚地弓线虫的激酶目标

来源:Nature中文 2010-05-20 12:21

原生动物“刚地弓线虫”(人体中的一种机会主义病原体)分泌被称为“微丝”的细胞器,它们在寄生虫运动性、宿主-细胞入侵和退出中扮演一个关键角色。

现在,这个过程被发现涉及“刚地弓线虫”依赖于钙的蛋白激酶-1(TgCDPK1)。哺乳动物宿主中这个激酶家族的缺乏使得这一蛋白成为药物设计的一个有吸引力的目标。(生物谷Bioon.com)

生物谷推荐原文出处:

Nature doi:10.1038/nature09022

Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma
Sebastian Lourido1, Joel Shuman1, Chao Zhang2, Kevan M. Shokat2, Raymond Hui3 & L. David Sibley1

Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA
Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 94158, USA
Structural Genomics Consortium, University Toronto, MaRS South Tower, Suite 732, 101 College Street, Toronto, Canada M5G 1L7

Calcium-regulated exocytosis is a ubiquitous process in eukaryotes, whereby secretory vesicles fuse with the plasma membrane and release their contents in response to an intracellular calcium surge1. This process regulates various cellular functions such as plasma membrane repair in plants and animals2, 3, the discharge of defensive spikes in Paramecium4, and the secretion of insulin from pancreatic cells, immune modulators from lymphocytes, and chemical transmitters from neurons5. In animal cells, serine/threonine kinases including cAMP-dependent protein kinase, protein kinase C and calmodulin kinases have been implicated in calcium-signal transduction leading to regulated secretion1, 6, 7. Although plants and protozoa also regulate secretion by means of intracellular calcium, the method by which these signals are relayed has not been explained. Here we show that the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is an essential regulator of calcium-dependent exocytosis in this opportunistic human pathogen. Conditional suppression of TgCDPK1 revealed that it controls calcium-dependent secretion of specialized organelles called micronemes, resulting in a block of essential phenotypes including parasite motility, host-cell invasion, and egress. These phenotypes were recapitulated by using a chemical biology approach in which pyrazolopyrimidine-derived compounds specifically inhibited TgCDPK1 and disrupted the parasite’s life cycle at stages dependent on microneme secretion. Inhibition was specific to TgCDPK1, because expression of a resistant mutant kinase reversed sensitivity to the inhibitor. TgCDPK1 is conserved among apicomplexans and belongs to a family of kinases shared with plants and ciliates8, suggesting that related CDPKs may have a function in calcium-regulated secretion in other organisms. Because this kinase family is absent from mammalian hosts, it represents a validated target that may be exploitable for chemotherapy against T.?gondii and related apicomplexans.

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