Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases

	Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases
	Zhang, L; Wang, JC; Hou, L; Cao, PR; Wu, L; Zhang, QS; Yang, HY; Zang, Y; Ding, JP; Li, J
刊名	SCIENTIFIC REPORTS
	2015
卷号	5 期号:1 页码:10115-10115
通讯作者	Zang, Y (reprint author), Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, 189 Guo Shoujing Rd, Shanghai 201203, Peoples R China.,yzang@simm.ac.cn
英文摘要	The His-x-Asp (HxD) motif is one of the most conserved structural components of the catalytic core of protein kinases; however, the functional role of the conserved histidine is unclear. Here we report that replacement of the HxD-histidine with Arginine or Phenylalanine in Aurora A abolishes both the catalytic activity and auto-phosphorylation, whereas the Histidine-to-tyrosine impairs the catalytic activity without affecting its auto-phosphorylation. Comparisons of the crystal structures of wild-type (WT) and mutant Aurora A demonstrate that the impairment of the kinase activity is accounted for by (1) disruption of the regulatory spine in the His-to-Arg mutant, and (2) change in the geometry of backbones of the Asp-Phe-Gly (DFG) motif and the DFG-1 residue in the His-to-Tyr mutant. In addition, bioinformatics analyses show that the HxD-histidine is a mutational hotspot in tumor tissues. Moreover, the H174R mutation of the HxD-histidine, in the tumor suppressor LKB1 abrogates the inhibition of anchorage-independent growth of A549 cells by WT LKB1. Based on these data, we propose that the HxD-histidine is involved in a conserved inflexible organization of the catalytic core that is required for the kinase activity. Mutation of the HxD-histidine may also be involved in the pathogenesis of some diseases including cancer.
学科主题	Science & Technology - Other Topics
类目[WOS]	Multidisciplinary Sciences
关键词[WOS]	LUNG-CANCER ; ACTIVATION ; PHOSPHORYLATION ; MECHANISMS ; MUTATIONS ; INACTIVATION ; CONFORMATION ; DOMAIN
收录类别	SCI
语种	英语
WOS记录号	WOS:000354274000001
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/112]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Zhang, L,Wang, JC,Hou, L,et al. Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases[J]. SCIENTIFIC REPORTS,2015,5(1):10115-10115.
APA	Zhang, L.,Wang, JC.,Hou, L.,Cao, PR.,Wu, L.,...&Li, J.(2015).Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases.SCIENTIFIC REPORTS,5(1),10115-10115.
MLA	Zhang, L,et al."Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases".SCIENTIFIC REPORTS 5.1(2015):10115-10115.