Hernanz-Falcón Patricia, Rodríguez-Frade José Miguel, Serrano Antonio, Juan David, del Sol Antonio, Soriano Silvia F, Roncal Fernando, Gómez Lucio, Valencia Alfonso, Martínez-A Carlos, Mellado Mario
Department of Immunology and Oncology, National Center of Biotechnology, Campus Universitario de Cantoblanco, E-28049 Madrid, Spain.
Nat Immunol. 2004 Feb;5(2):216-23. doi: 10.1038/ni1027. Epub 2004 Jan 11.
Chemokines coordinate leukocyte trafficking by promoting oligomerization and signaling by G protein-coupled receptors; however, it is not known which amino acid residues of the receptors participate in this process. Bioinformatic analysis predicted that Ile52 in transmembrane region-1 (TM1) and Val150 in TM4 of the chemokine receptor CCR5 are key residues in the interaction surface between CCR5 molecules. Mutation of these residues generated nonfunctional receptors that could not dimerize or trigger signaling. In vitro and in vivo studies in human cell lines and primary T cells showed that synthetic peptides containing these residues blocked responses induced by the CCR5 ligand CCL5. Fluorescence resonance energy transfer showed the presence of preformed, ligand-stabilized chemokine receptor oligomers. This is the first description of the residues involved in chemokine receptor dimerization, and indicates a potential target for the modification of chemokine responses.
趋化因子通过促进寡聚化以及经由G蛋白偶联受体进行信号传导来协调白细胞运输；然而，尚不清楚受体的哪些氨基酸残基参与这一过程。生物信息学分析预测，趋化因子受体CCR5跨膜区1（TM1）中的Ile52和TM4中的Val150是CCR5分子间相互作用表面的关键残基。这些残基的突变产生了无法二聚化或触发信号传导的无功能受体。在人类细胞系和原代T细胞中进行的体外和体内研究表明，含有这些残基的合成肽可阻断CCR5配体CCL5诱导的反应。荧光共振能量转移显示存在预先形成的、由配体稳定的趋化因子受体寡聚体。这是对参与趋化因子受体二聚化的残基的首次描述，并表明了一个用于修饰趋化因子反应的潜在靶点。
