The inositol pyrophosphate 5-InsP(7) drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α.
The inositol pyrophosphate 5-InsP(7) drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α.
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肌醇焦磷酸 5-InsP7 通过缓解 PI3K p85α 的自抑制域来驱动钠钾泵降解
DOI：
10.1126/sciadv.abb8542
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发表时间：
2020-10
期刊：
影响因子：
13.6
通讯作者：
Fu C
中科院分区：
文献类型：
--
作者：
Chin AC;Gao Z;Riley AM;Furkert D;Wittwer C;Dutta A;Rojas T;Semenza ER;Felder RA;Pluznick JL;Jessen HJ;Fiedler D;Potter BVL;Snyder SH;Fu C
5-InsP7是Na+/K+- atp酶的内源性负调节因子。钠/钾转运腺苷三磷酸酶（Na+/K+- atp酶）是最丰富的细胞膜蛋白之一，对真核生物至关重要。长期以来，人们一直认为内源性负调节因子在调节Na+/K+- atp酶的活性和稳定性方面发挥重要作用，但这些调节因子的表征一直难以捉摸。调节Na+/K+- atp酶稳态转换的机制尚不清楚。在这里，我们报道了由肌醇己基磷酸激酶1 （IP6K1）产生的5-二磷酸肌醇1,2,3,4,6-五磷酸肌醇（5-InsP7），促进生理内吞和Na+/K+- atp酶-α1的下游降解。IP6K1的缺失导致多种组织和细胞类型的质膜中Na+/K+- atp酶-α1的两倍富集。利用一套合成化学生物学工具，我们发现5-InsP7结合磷脂酰肌醇3-激酶（PI3K） p85α的RhoGAP结构域，解除了其与Na+/K+- atp酶-α1的相互作用。这招募了适配蛋白2 （AP2）并触发了网格蛋白介导的Na+/K+- atp酶-α1的内吞作用。我们的研究发现5-InsP7是内源性Na+/K+- atp酶-α1的负调节因子。
5-InsP7 is an endogenous negative regulator of Na+/K+-ATPase. Sodium/potassium-transporting adenosine triphosphatase (Na+/K+-ATPase) is one of the most abundant cell membrane proteins and is essential for eukaryotes. Endogenous negative regulators have long been postulated to play an important role in regulating the activity and stability of Na+/K+-ATPase, but characterization of these regulators has been elusive. Mechanisms of regulating Na+/K+-ATPase homeostatic turnover are unknown. Here, we report that 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-InsP7), generated by inositol hexakisphosphate kinase 1 (IP6K1), promotes physiological endocytosis and downstream degradation of Na+/K+-ATPase-α1. Deletion of IP6K1 elicits a twofold enrichment of Na+/K+-ATPase-α1 in plasma membranes of multiple tissues and cell types. Using a suite of synthetic chemical biology tools, we found that 5-InsP7 binds the RhoGAP domain of phosphatidylinositol 3-kinase (PI3K) p85α to disinhibit its interaction with Na+/K+-ATPase-α1. This recruits adaptor protein 2 (AP2) and triggers the clathrin-mediated endocytosis of Na+/K+-ATPase-α1. Our study identifies 5-InsP7 as an endogenous negative regulator of Na+/K+-ATPase-α1.
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影响因子：
7.3
作者：
Chakraborty A;Kim S;Snyder SH
通讯作者：
Snyder SH
内源性数字般的因素：历史的概述。
影响因子：
5.2
作者：
Buckalew VM
通讯作者：
Buckalew VM
影响因子：
64.5
作者：
Chakraborty A;Koldobskiy MA;Bello NT;Maxwell M;Potter JJ;Juluri KR;Maag D;Kim S;Huang AS;Dailey MJ;Saleh M;Snowman AM;Moran TH;Mezey E;Snyder SH
通讯作者：
Snyder SH
DOI：
10.1165/rcmb.2008-0365oc
发表时间：
2009-12-01
影响因子：
6.4
作者：
Lecuona, Emilia;Sun, Haiying;Sznajder, Jacob I.
通讯作者：
Sznajder, Jacob I.
影响因子：
3.6
作者：
Choi, Kuicheon;Mollapour, Elahe;Shears, Stephen B.
通讯作者：
Shears, Stephen B.