Molecular basis for PP2A regulatory subunit B56α targeting in cardiomyocytes
Molecular basis for PP2A regulatory subunit B56α targeting in cardiomyocytes
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DOI：
10.1152/ajpheart.00059.2007
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发表时间：
2007-07-01
影响因子：
4.8
通讯作者：
Mohler, Peter J.
中科院分区：
文献类型：
--
作者：
Bhasin, Naina;Cunha, Shane R.;Mohler, Peter J.
蛋白磷酸酶2A（PP 2A）是一种多功能蛋白磷酸酶，在可兴奋细胞信号传导中起关键作用。在心脏中，PP 2A功能与β-肾上腺素能信号传导的调节有关，并已被认为调节关键离子通道和转运蛋白，包括Na/Ca交换剂、兰尼碱受体、肌醇1，4，5-三磷酸受体和Na/K ATP酶。虽然PP 2A在心脏中的许多功能作用和分子靶点是已知的，但关于将特定PP 2A亚型活性定位于亚细胞位点的细胞途径却很少建立。我们报告说，PP 2A调节亚基B56 α是一个在体内的结合伙伴，为锚定B，一个衔接蛋白需要正常的亚细胞定位的Na/Ca交换，Na/K ATP酶，和肌醇1，4，5-三磷酸受体。锚蛋白-B和B56 α在原代心肌细胞中共定位和共免疫沉淀。使用多种策略，我们确定了B56 α上的结构要求，作为B56 α COOH末端的13个残基序，在其他B56家族多肽中不存在于B56 α-B结合。最后，我们报告说，在原代ankrex-B +/-心肌细胞中，ankrex-B表达的减少导致B56 α的无序分布，这可以通过ankrex-B的外源性表达来挽救。这些新的数据暗示锚蛋白-B是心脏中PP 2A的关键靶向组分，并鉴定了一类新的锚蛋白多肽靶向的信号蛋白。
Protein phosphatase 2A (PP2A)is a multifunctional protein phosphatase with critical roles in excitable cell signaling. In the heart, PP2A function is linked with modulation of beta-adrenergic signaling and has been suggested to regulate key ion channels and transporters including Na/Ca exchanger, ryanodine receptor, inositol 1,4,5-trisphosphate receptor, and Na/K ATPase. Although many of the functional roles and molecular targets for PP2A in heart are known, little is established regarding the cellular pathways that localize specific PP2A isoform activities to subcellular sites. We report that the PP2A regulatory subunit B56 alpha is an in vivo binding partner for ankyrin-B, an adapter protein required for normal subcellular localization of the Na/Ca exchanger, Na/K ATPase, and inositol 1,4,5-trisphosphate receptor. Ankyrin-B and B56 alpha are colocalized and coimmunoprecipitate in primary cardiomyocytes. Using multiple strategies, we identified the structural requirements on B56 alpha for ankyrin-B association as a 13 residue motif in the B56 alpha COOH terminus not present in other B56 family polypeptides. Finally, we report that reduced ankyrin-B expression in primary ankyrin-B+/- cardiomyocytes results in disorganized distribution of B56 alpha that can be rescued by exogenous expression of ankyrin-B. These new data implicate ankyrin-B as a critical targeting component for PP2A in heart and identify a new class of signaling proteins targeted by ankyrin polypeptides.