The conserved isoleucine-valine-phenylalanine motif couples activation state and endocytic functions of β-arrestins
The conserved isoleucine-valine-phenylalanine motif couples activation state and endocytic functions of β-arrestins
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DOI：
10.1111/j.1600-0854.2007.00578.x
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发表时间：
2007-07-01
期刊：
影响因子：
4.5
通讯作者：
Benmerah, Alexandre
中科院分区：
文献类型：
--
作者：
Burtey, Anne;Schmid, Eva M.;Benmerah, Alexandre
β-阻滞素(β-ARRs)在G蛋白偶联受体(GPCRs)的调节中起核心作用。它们与磷酸化激活的GPCRs结合，诱导构象转变为活性状态，导致其柔性C末端尾巴的释放。然后，揭示了网状蛋白和适配器蛋白(AP)-2网状蛋白适配器复合体的结合部位，这推动了βARRS-GPCR复合体的募集到网状蛋白包被的坑(CCP)中。C末端尾部的保守的异亮氨酸-缬氨酸-苯丙氨酸(IVF)基序通过分子内相互作用控制β-ARR的激活。在这里，我们提供了活细胞的结构、生化和功能证据，证明体外受精基序也控制与AP-2的结合。虽然F残基直接参与AP-2的结合，但I和V残基的取代显著增强了与AP-2的亲和力，导致了活性的βarr突变体，这些突变体在没有任何GPCR激活的情况下结构性地靶向CCP。因此，β受体的构象变化和内吞功能似乎是通过体外受精基序建立的复杂分子相互作用来协调的。
Beta-arrestins (beta arrs) play a central role in the regulation of G-protein-coupled receptors (GPCRs). Their binding to phosphorylated activated GPCRs induces a conformational transition to an active state resulting in the release of their flexible C-terminal tail. Binding sites for clathrin and the adaptor protein (AP)-2 clathrin adaptor complex are then unmasked, which drive the recruitment of beta arrs-GPCR complexes into clathrin-coated pits (CCPs). A conserved isoleucine-valine-phenylalanine (IVF) motif of the C-terminal tail controls beta arr activation through intramolecular interactions. Here, we provide structural, biochemical and functional evidence in living cells that the IVF motif also controls binding to AP-2. While the F residue is directly involved in AP-2 binding, substitutions of I and V residues, markedly enhanced affinity for AP-2 resulting in active beta arr mutants, which are constitutively targeted to CCPs in the absence of any GPCR activation. Conformational change and endocytic functions of beta arrs thus appear to be coordinated via the complex molecular interactions established by the IVF motif.