Phospholamban inhibitory function is activated by depolymerization
Phospholamban inhibitory function is activated by depolymerization
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DOI：
10.1074/jbc.272.24.15061
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发表时间：
1997-06-13
影响因子：
4.8
通讯作者：
MacLennan, DH
中科院分区：
文献类型：
--
作者：
Kimura, Y;Kurzydlowski, K;MacLennan, DH
受磷蛋白（Phospholamban，PLN）是一种五聚体的膜蛋白，通过膜内相互作用可逆地抑制心肌肌浆网Ca ~（2+）-ATP酶（SERCA 2a）的活性。一面中的突变减少了与SERCA 2a的跨膜序列的抑制性相互作用，但对五聚体状态的影响相对较小，而另一面中的突变激活了抑制性相互作用并增强了单体形成。双突变体是单体的，但抑制功能的丧失相对于抑制功能的激活是显性的，这些观察结果支持SERCA 2a相互作用位点位于螺旋面上的提议，其不参与五聚体的形成。四种高度抑制性突变体有效地缺乏五聚体，表明五聚体PLN代表较低活性或无活性的储库，其解离以提供抑制性单体PLN亚基。提出了一种模型，其中PLN对SERCA 2a活性的抑制程度最终由被抑制的PLN单体SERCA 2a异二聚体复合物的浓度决定，该抑制复合物的浓度由PLN五聚体（其是突变敏感的）的解离常数和PLN/SERCA 2a异二聚体（其可能是突变敏感的）的解离常数确定。
Phospholamban (PLN), a homopentameric, integral membrane protein, reversibly inhibits cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity through intramembrane interactions, Here, alanine-scanning mutagenesis of the PLN transmembrane sequence was used to identify two functional domains on opposite faces of the transmembrane helix. Mutations in one face diminish inhibitory interactions with transmembrane sequences of SERCA2a, but have relatively little effect on the pentameric state, while mutations in the other face activate inhibitory interactions and enhance monomer formation, Double mutants are monomeric, but loss of inhibitory function is dominant over activation of inhibitory function, These observations support the proposal that the SERCA2a interaction site lies on the helical face which is not involved in pentamer formation, Four highly inhibitory mutants are effectively devoid of pentamer, suggesting that pentameric PLN represents a less active or inactive reservoir that dissociates to provide inhibitory monomeric PLN subunits, A model is presented in which the degree of PLN inhibition of SERCA2a activity is ultimately determined by the concentration of the inhibited PLN monomer SERCA2a heterodimeric complex, The concentration of this inhibited complex is determined by the dissociation constant for the PLN pentamer (which is mutation-sensitive) and by the dissociation constant for the PLN/SERCA2a heterodimer (which is likely to be mutation-sensitive).