SR蛋白
激酶
细胞周期蛋白依赖激酶
生物
葛兰素史克-3
丝氨酸
生物化学
选择性拼接
DYRK1A型
磷酸化
基因亚型
基因
细胞周期
作者
Pritesh Jain,Chandrabose Karthikeyan,N. S. Hari Narayana Moorthy,Digambar Kumar Waiker,Arvind Kumar Jain,Piyush Trivedi
出处
期刊:Current Drug Targets
[Bentham Science]
日期:2014-04-01
卷期号:15 (5): 539-550
被引量:74
标识
DOI:10.2174/1389450115666140226112321
摘要
The cdc2-like kinases (CLKs) are an evolutionarily conserved group of dual specificity kinases belonging to the CMGC (cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases). The CLK family consists of four isoforms namely CLK1, CLK2, CLK3 and CLK4. The human CLK1 encoded protein comprises 454 amino acids and the catalytic domain of CLK1 exhibits the typical protein kinase fold. CLK1 has been shown to autophosphorylate on serine, threonine and tyrosine residues and phosphorylate exogenous substrates on serine and threonine residues. CLK1 plays an important role in the regulation of RNA splicing through phosphorylation of members of the serine and arginine-rich (SR) family of splicing factors. CLK1 is involved in the pathophysiology of Alzheimer’s disease by phosphorylating the serine residue in SR proteins. Nuclear speckles of the nucleoplasm contain the stored form of SR proteins and are moderately responsible for the choice of splicing sites during pre-mRNA splicing. Hence, the inhibition of CLK1 can be used as a therapeutic strategy for Alzheimer’s disease. Many natural and synthetic molecules are reported to possess CLK1 inhibitory activity. Some specific examples are Marine alkaloid Leucettamine B and KH-CB19. Leucettamine B is a potent inhibitor of CLK1 (15 nM), Dyrk1A (40 nM), and Dyrk2 (35 nM) and a moderate inhibitor of CLK3 (4.5 µM) whereas KH-CB19 is a highly specific and potent inhibitor of the CLK1/CLK4. X-ray crystallographic studies have revealed the binding mode of marine sponge metabolite hymenialdisine and a dichloroindolyl enamino nitrile (KH-CB19) to CLK1. This review focuses on the role of CLKs in the pathophysiology of Alzheimer's disease and therapeutic potential of targeting CLK1 in Alzheimer's disease drug discovery and development. In addition, the recent developments in drug discovery efforts targeting human CLK1 are also highlighted. Keywords: Cdc2 like kinase (CLK), Alzheimer’s disease, SR proteins, protein kinases, CLK1 inhibitors.
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