MRC Laboratory of Molecular Biology, Cambridge, UK.
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
Nat Struct Mol Biol. 2018 Jun;25(6):538-545. doi: 10.1038/s41594-018-0071-3. Epub 2018 Jun 5.
Arrestins regulate the signaling of ligand-activated, phosphorylated G-protein-coupled receptors (GPCRs). Different patterns of receptor phosphorylation (phosphorylation barcode) can modulate arrestin conformations, resulting in distinct functional outcomes (for example, desensitization, internalization, and downstream signaling). However, the mechanism of arrestin activation and how distinct receptor phosphorylation patterns could induce different conformational changes on arrestin are not fully understood. We analyzed how each arrestin amino acid contributes to its different conformational states. We identified a conserved structural motif that restricts the mobility of the arrestin finger loop in the inactive state and appears to be regulated by receptor phosphorylation. Distal and proximal receptor phosphorylation sites appear to selectively engage with distinct arrestin structural motifs (that is, micro-locks) to induce different arrestin conformations. These observations suggest a model in which different phosphorylation patterns of the GPCR C terminus can combinatorially modulate the conformation of the finger loop and other phosphorylation-sensitive structural elements to drive distinct arrestin conformation and functional outcomes.
抑制蛋白调节配体激活的、磷酸化的 G 蛋白偶联受体 (GPCR) 的信号转导。不同的受体磷酸化模式 (磷酸化条码) 可以调节抑制蛋白构象，从而产生不同的功能结果(例如脱敏、内化和下游信号转导)。然而，抑制蛋白的激活机制以及不同的受体磷酸化模式如何诱导抑制蛋白的不同构象变化尚不完全清楚。我们分析了抑制蛋白的每个氨基酸如何对其不同的构象状态做出贡献。我们确定了一个保守的结构模体，该模体限制了抑制蛋白指环在非活性状态下的移动性，并且似乎受到受体磷酸化的调节。远端和近端的受体磷酸化位点似乎选择性地与不同的抑制蛋白结构模体 (即微锁) 结合，以诱导不同的抑制蛋白构象。这些观察结果表明，一种模型可以解释 GPCR C 末端的不同磷酸化模式如何组合调节指环的构象和其他磷酸化敏感的结构元件，从而驱动不同的抑制蛋白构象和功能结果。
