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首页> 外文期刊>The FEBS journal >Direct association of the unique C-terminal tail oftransmembrane AMPA receptor regulatory protein c-8 withcalcineurin
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Direct association of the unique C-terminal tail oftransmembrane AMPA receptor regulatory protein c-8 withcalcineurin

机译：跨膜AMPA受体调节蛋白c-8的独特C末端尾巴与钙调神经磷酸酶直接缔合

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Transmembrane a-amino-3-hydroxy-5-methyl-4-isoxazole propionate(AMPA) receptor regulatory proteins (TARPs) are auxiliary subunits thatregulate AMPA receptor trafficking to the plasma membrane and localizationto postsynaptic sites. The classical TARP family consists of four members:stargazin/c-2, c-3, c-4 and c-8. The TARP c-8 isoform, which ishighly expressed in the hippocampus, has a unique, long C-terminaldomain with five distinct regions: two glycine-rich regions, a serine/arginine-rich region, a proline/alanine (P/A) rich region, and a PSD-95/Dlg/ZO-1 (PDZ) binding motif. We performed mass spectrometry andimmunoprecipitation assays to identify specific binding partners for the c-8C-terminal tail and found that c-8, but not stargazin/c-2, co-immunoprecipitatedwith calcineurin/PP2B, a Ca2+/calmodulin-dependent Ser/Thrphosphatase. Co-immunoprecipitation and immunoblot analyses of lysatesfrom COS-7 cells co-transfected with calcineurin and either wild-type orchimeric c-8 revealed that a section of the C-terminal tail (residues 356–421)can bind calcineurin. Futhermore, c-8 lacking the P/A-rich region (residues383–399) did not bind to calcineurin. In addition, the GST-c-8 C-terminaltail (residues 353–414) fusion protein containing the P/A-rich region boundto purified calcineurin in a Ca2+/calmodulin-dependent manner, whereasGST-c-8 with a deletion of the P/A-rich region did not. Peptide competitionassays demonstrated that c-8 may interact with the hydrophobic pocketdefined by b-sheet 14 and/or adjacent regions of the catalytic A subunit ofcalcineurin. These results indicate that the c-8 P/A-rich region is essentialfor binding calcineurin, suggesting that the c-8/calcineurin complex mayregulate AMPA receptor phosphorylation and trafficking.
机译：跨膜丙酸α-氨基-3-羟基-5-甲基-4-异恶唑（AMPA）受体调节蛋白（TARPs）是辅助亚基，可调节AMPA受体向质膜的运输并定位于突触后部位。经典的TARP家族由四个成员组成：stargazin / c-2，c-3，c-4和c-8。 TARP c-8亚型在海马中高度表达，具有独特的长C端结构域，具有五个不同区域：两个富含甘氨酸的区域，一个富含丝氨酸/精氨酸的区域，一个脯氨酸/丙氨酸（P / A）丰富的区域，以及PSD-95 / Dlg / ZO-1（PDZ）结合基序。我们进行了质谱和免疫沉淀测定，以鉴定c-8C末端尾巴的特异性结合配偶体，发现c-8（而不是stargazin / c-2）与钙调神经磷酸酶/ PP2B，Ca2 + /钙调蛋白依赖性Ser / Thr磷酸酶共免疫沉淀。 。钙调神经磷酸酶和野生型嵌合c-8共转染的COS-7细胞裂解物的共免疫沉淀和免疫印迹分析表明，C末端尾巴的一部分（残基356-421）可以结合钙调神经磷酸酶。此外，缺少富含P / A区域（残基383–399）的c-8不能与钙调神经磷酸酶结合。此外，GST-c-8 C-末端（残基353-414）融合蛋白含有富含P / A的区域，以Ca2 + /钙调蛋白依赖性的方式与纯化的钙调神经磷酸酶结合，而GST-c-8缺失了P / A丰富的区域没有。肽竞争测定表明，c-8可能与b-sheet 14和/或钙调神经磷酸酶催化A亚基的相邻区域所定义的疏水口袋相互作用。这些结果表明，富含c-8 P / A的区域对于结合钙调神经磷酸酶是必不可少的，这表明c-8 /钙调神经磷酸酶复合物可以调节AMPA受体的磷酸化和运输。

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