Structure of phospholipase Cε reveals an integrated RA1 domain and previously unidentified regulatory elements.
Structure of phospholipase Cε reveals an integrated RA1 domain and previously unidentified regulatory elements.
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磷脂酶 Cβ 的结构揭示了集成的 RA1 结构域和以前未识别的调节元件。
DOI：
10.1038/s42003-020-01178-8
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发表时间：
2020
影响因子：
5.9
通讯作者：
Lyon,AngelineM
中科院分区：
文献类型：
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作者：
Rugema,NgangoY;Garland-Kuntz,ElisabethE;Sieng,Monita;Muralidharan,Kaushik;VanCamp,MichelleM;O'Neill,Hannah;Mbongo,William;Selvia,ArielleF;Marti,AndreaT;Everly,Amanda;McKenzie,Emmanda;Lyon,AngelineM
磷脂酶Cε(PLCε)在心血管系统的血浆和核周膜上产生脂质衍生的第二信使。它通过涉及其c端Ras关联（RA）结构域（RA1和RA2）的机制，响应各种各样的信号，例如Rap1A和Ras传递的信号。然而，plc的体积和复杂性阻碍了其结构和功能的分析。在此，我们报道了plcε最小片段的2.7 Å晶体结构，保留了基础活性。该结构包括RA1域，它与其他核心域形成广泛的相互作用。在plcε的自调节X-Y连接体中也发现了一个保守的两亲螺旋，我们发现它在体外和细胞中调节活性。这些研究为这种关键心血管酶的核心提供了结构框架，这将使我们更好地了解其在疾病中的调节和作用。
Phospholipase Cε(PLCε) generates lipid-derived second messengers at the plasma and perinuclear membranes in the cardiovascular system. It is activated in response to a wide variety of signals, such as those conveyed by Rap1A and Ras, through a mechanism that involves its C-terminal Ras association (RA) domains (RA1 and RA2). However, the complexity and size of PLCεhas hindered its structural and functional analysis. Herein, we report the 2.7 Å crystal structure of the minimal fragment of PLCεthat retains basal activity. This structure includes the RA1 domain, which forms extensive interactions with other core domains. A conserved amphipathic helix in the autoregulatory X–Y linker of PLCεis also revealed, which we show modulates activity in vitro and in cells. The studies provide the structural framework for the core of this critical cardiovascular enzyme that will allow for a better understanding of its regulation and roles in disease.