New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model.
New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model.
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DOI：
10.1016/j.bcp.2016.04.007
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发表时间：
2016-08-15
影响因子：
5.8
通讯作者：
Volkman, Brian F.
中科院分区：
文献类型：
--
作者：
Kleist, Andrew B.;Getschman, Anthony E.;Ziarek, Joshua J.;Nevins, Amanda M.;Gauthier, Pierre-Arnaud;Chevigne, Andy;Szpakowska, Martyna;Volkman, Brian F.
关键词：
趋化因子受体（CKR）信号传导形成基本免疫细胞功能的基础，并且失调的CKR信号传导支持免疫系统及其他的许多疾病过程。属于七跨膜结构域受体（7 TMR）超家族的CKR在内源性分泌的趋化因子配体结合后启动信号传导。趋化因子-CKR相互作用传统上通过两步/两位点机制来描述，其中CKR N-末端识别趋化因子球状核心（即位点1相互作用），然后当非结构化趋化因子N-末端插入受体TM束中时激活（即位点2相互作用）。最近的几项研究挑战网站1和2的结构独立性，证明这些所谓的独立网站之间的物理和变构联系。其他人则质疑这些网站的功能独立性，确定了CKR激活中网站1和其他相互作用的细微差别。这些发展出现在一个快速变化的景观中，其中CKR信号传导受受体PTM，趋化因子和CKR二聚化以及内源性非趋化因子配体的影响。7 TMR偏置信号的结构和功能表征的同时进展改变了我们对混杂趋化因子-CKR相互作用的理解。在这篇综述中，我们探讨新的范例CKR信号转导的研究，描绘了一个更复杂的架构管理趋化因子CKR相互作用的后果。
Chemokine receptor (CKR) signaling forms the basis of essential immune cellular functions, and dysregulated CKR signaling underpins numerous disease processes of the immune system and beyond. CKRs, which belong to the seven transmembrane domain receptor (7TMR) superfamily, initiate signaling upon binding of endogenous, secreted chemokine ligands. Chemokine-CKR interactions are traditionally described by a two-step/two-site mechanism, in which the CKR N-terminus recognizes the chemokine globular core (i.e. site 1 interaction), followed by activation when the unstructured chemokine N-terminus is inserted into the receptor TM bundle (i.e. site 2 interaction). Several recent studies challenge the structural independence of sites 1 and 2 by demonstrating physical and allosteric links between these supposedly separate sites. Others contest the functional independence of these sites, identifying nuanced roles for site 1 and other interactions in CKR activation. These developments emerge within a rapidly changing landscape in which CKR signaling is influenced by receptor PTMs, chemokine and CKR dimerization, and endogenous non-chemokine ligands. Simultaneous advances in the structural and functional characterization of 7TMR biased signaling have altered how we understand promiscuous chemokine-CKR interactions. In this review, we explore new paradigms in CKR signal transduction by considering studies that depict a more intricate architecture governing the consequences of chemokine-CKR interactions.
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