Phosphorylation Barcoding as a Mechanism of Directing GPCR Signaling
Phosphorylation Barcoding as a Mechanism of Directing GPCR Signaling
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DOI：
10.1126/scisignal.2002331
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发表时间：
2011-08-09
影响因子：
7.3
通讯作者：
Liggett, Stephen B.
中科院分区：
文献类型：
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作者：
Liggett, Stephen B.
G蛋白偶联受体（GPCRs）以细胞类型依赖性和G蛋白非依赖性方式发出信号的统一机制在过去十年中得到了发展。GPCR激酶（GRK）是同源脱敏的介质：受体的GRK磷酸化导致随后的β-抑制蛋白结合，其部分淬灭受体与G蛋白的偶联。对于某些受体，这种GRK介导的磷酸化通过β-抑制蛋白的支架作用刺激额外的信号传导。这些下游信号由β-抑制蛋白构象配置，其由受体上的GRK磷酸受体以条形码样方式决定。此外，每个GRK可以潜在地磷酸化给定受体上的不同丝氨酸和苏氨酸残基，并且磷酸化模式可以通过由结合的配体建立的受体构象而偏向。最后，潜在的GRK磷酸化位点的排列，以及β-arrestin的构象及其对下游信号的影响，即使在相同激动剂刺激的密切相关的GPCR之间也会有很大的不同。柔性β-抑制蛋白条形码的多样性解释了超家族中信号传导的多维性质，并代表了药物发现的新机会。
A unifying mechanism by which G protein-coupled receptors (GPCRs) signal in cell type-dependent and G protein-independent ways has developed over the past decade. GPCR kinases (GRKs) are mediators of homologous desensitization: GRK phosphorylation of the receptors leads to the subsequent binding of beta-arrestins, which partially quenches receptor coupling to G proteins. For some receptors, this GRK-mediated phosphorylation stimulates additional signaling through the scaffolding action of beta-arrestin. These downstream signals are configured by beta-arrestin conformation, which is dictated by the GRK phosphoacceptors on the receptors in a barcode-like fashion. Furthermore, each of the GRKs can potentially phosphorylate different serine and threonine residues on a given receptor, and the phosphorylation pattern can be biased by the receptor conformation established by bound ligand. Finally, the arrangement of potential GRK phosphorylation sites-and thus the conformation of beta-arrestin and its effect on downstream signaling-can differ substantially between even closely related GPCRs stimulated by the same agonist. The diversity of the barcoding to flexible beta-arrestin explains the multidimensional nature of signaling in the superfamily and represents new opportunities for drug discovery.