Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes.
Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes.
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蛋白质磷酸酶5在心肌细胞中调节与肌膜相关的机械传感器复合物的钛磷酸化和功能。
DOI：
10.1038/s41467-017-02483-3
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发表时间：
2018-01-17
影响因子：
16.6
通讯作者：
Linke WA
中科院分区：
文献类型：
--
作者：
Krysiak J;Unger A;Beckendorf L;Hamdani N;von Frieling-Salewsky M;Redfield MM;Dos Remedios CG;Sheikh F;Gergs U;Boknik P;Linke WA
丝氨酸/苏氨酸蛋白磷酸酶5 （PP5）在真核细胞中普遍表达；然而，其在心肌细胞中的功能尚不清楚。在基础条件下，PP5被自身抑制，但酶活性在结合特定因子（如伴侣蛋白Hsp90）后上升。在这里，我们发现PP5结合并去磷酸化心肌细胞中肌凝素的弹性n2b独特序列（N2Bus）。通过各种结合和磷酸化试验、细胞培养操作和转基因小鼠心脏，我们证明PP5在体外和肉瘤中与N2Bus相关，并且对几种蛋白激酶具有拮抗作用，这些蛋白激酶磷酸化N2Bus并降低titin基被动张力。PP5在病理性上升高，可能导致人类衰竭心脏N2Bus的低磷酸化。此外，hsp90激活的PP5与一种肉瘤、n2bus相关的机械传感器复合体的组分相互作用，并阻断该复合体中有丝分裂原激活的蛋白激酶信号传导。我们的工作证实了PP5是心肌细胞中一种区隔化的、控制良好的磷酸酶，它调节肌丝中的titin特性和激酶信号。蛋白磷酸酶5 （PP5）在许多细胞类型中表达，但其在心肌细胞中的作用尚不清楚。在这里，作者表明PP5在心肌肌瘤中结合并使弹性titin去磷酸化，并且PP5在心力衰竭时增加，降低心肌细胞的顺应性。
Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension. PP5 is pathologically elevated and likely contributes to hypo-phosphorylation of N2Bus in failing human hearts. Furthermore, Hsp90-activated PP5 interacts with components of a sarcomeric, N2Bus-associated, mechanosensor complex, and blocks mitogen-activated protein-kinase signaling in this complex. Our work establishes PP5 as a compartmentalized, well-controlled phosphatase in cardiomyocytes, which regulates titin properties and kinase signaling at the myofilaments. Protein phosphatase 5 (PP5) is expressed in many cell types but its role in cardiomyocytes is unknown. Here the authors show that PP5 binds and dephosphorylates elastic titin in cardiac sarcomeres, and that PP5 is increased in heart failure, reducing cardiomyocyte compliance.
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影响因子：
11.4
作者：
Bueno, OF;De Windt, LJ;Molkentin, JD
通讯作者：
Molkentin, JD
调节调节剂：对心脏蛋白磷酸酶1相互作用的见解。
影响因子：
5
作者：
Chiang, David Y.;Heck, Albert J. R.;Dobrev, Dobromir;Wehrens, Xander H. T.
通讯作者：
Wehrens, Xander H. T.
影响因子：
20.1
作者：
Hidalgo C;Hudson B;Bogomolovas J;Zhu Y;Anderson B;Greaser M;Labeit S;Granzier H
通讯作者：
Granzier H
影响因子：
20.1
作者：
Hamdani, Nazha;Krysiak, Judith;Linke, Wolfgang A.
通讯作者：
Linke, Wolfgang A.
影响因子：
3.4
作者：
Gruetzner, Anika;Garcia-Manyes, Sergi;Linke, Wolfgang A.
通讯作者：
Linke, Wolfgang A.