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Constitutive activation of CCR5 and CCR2 induced by conformational changes in the conserved TXP motif in transmembrane helix 2

文献类型:期刊论文

作者Arias, DA; Navenot, JM; Zhang, WB; Broach, J; Peiper, SC
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
出版日期2003
卷号278期号:38页码:36513-36521
通讯作者Peiper, SC (reprint author), Med Coll Georgia, Dept Pathol, Augusta, GA 30912 USA.,
英文摘要CCR5 is a G protein-coupled receptor for RANTES, MIP-1alpha, MIP-1beta, and MCP-2 that functions as the front line coreceptor for human immunodeficiency virus type 1 infection. To elucidate the mechanism for CCR5 activation, this coreceptor was expressed in yeast coupled to the pheromone response pathway and a constitutively active mutant (CAM) was derived by random mutagenesis. Conversion of Thr-82 in the highly conserved TXP motif in transmembrane helix 2 to Pro, His, Tyr, Arg, or Lys conferred autonomous signaling activity in yeast and mammalian cells. This substitution also imparted constitutive signaling to CCR2 in yeast and mammalian cells, but not CCR1, CCR3, CCR4, CXCR2, or CXCR4. The CCR5-CAM, but not the CCR2-CAM had a reduction in ligand binding affinity. Whereas the amplitude of calcium mobilization induced by RANTES stimulation was lower in the CCR5-CAM than the wild-type (WT) receptor, MCP-1 induced a higher signal in the CCR2-CAM than in CCR2-WT. The chemotactic response of CCR5-CAM(T82P) to RANTES was similar to that of CCR5-WT, but CCR5-CAM(T82K) was dramatically decreased. The chemotactic response of CCR2-WT and CCR2-CAM(T94K) were similar. These findings extend insight into the role of the TXP motif in the mechanism for CCR5 signaling. CCR2, the receptor most closely genetically related to CCR5, shared a similar signaling mechanism, but other receptors containing the TXP motif did not. The expression of CCR5 and CCR2 in yeast and the availability of variants with autonomous signaling represent critical tools for characterizing receptor antagonists and developing approaches to block their role in human diseases.
学科主题Biochemistry & Molecular Biology
类目[WOS]Biochemistry & Molecular Biology
关键词[WOS]HUMAN-IMMUNODEFICIENCY-VIRUS ; PROTEIN-COUPLED RECEPTOR ; AMINO-TERMINAL DOMAIN ; MACROPHAGE-TROPIC HIV ; II TYPE-1 RECEPTOR ; CHEMOKINE-RECEPTOR ; ENVELOPE GLYCOPROTEIN ; C5A RECEPTOR ; N-TERMINUS ; CORECEPTOR
收录类别SCI
语种英语
WOS记录号WOS:000185318300080
版本出版稿
源URL[http://202.127.25.143/handle/331003/2391]  
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
Arias, DA,Navenot, JM,Zhang, WB,et al. Constitutive activation of CCR5 and CCR2 induced by conformational changes in the conserved TXP motif in transmembrane helix 2[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2003,278(38):36513-36521.
APA Arias, DA,Navenot, JM,Zhang, WB,Broach, J,&Peiper, SC.(2003).Constitutive activation of CCR5 and CCR2 induced by conformational changes in the conserved TXP motif in transmembrane helix 2.JOURNAL OF BIOLOGICAL CHEMISTRY,278(38),36513-36521.
MLA Arias, DA,et al."Constitutive activation of CCR5 and CCR2 induced by conformational changes in the conserved TXP motif in transmembrane helix 2".JOURNAL OF BIOLOGICAL CHEMISTRY 278.38(2003):36513-36521.

入库方式: OAI收割

来源:上海生物化学与细胞生物学研究所

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