Palmitoylation and Membrane Binding of Arc/Arg3.1: A Potential Role in Synaptic Depression.
Palmitoylation and Membrane Binding of Arc/Arg3.1: A Potential Role in Synaptic Depression.
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DOI：
10.1021/acs.biochem.7b00959
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发表时间：
2018-02-06
期刊：
影响因子：
2.9
通讯作者：
Albanesi, Joseph P.
中科院分区：
文献类型：
--
作者：
Barylko, Barbara;Wilkerson, Julia R.;Cavalier, Sheridan H.;Binns, Derk D.;James, Nicholas G.;Jameson, David M.;Huber, Kimberly M.;Albanesi, Joseph P.
活动调节细胞骨架相关蛋白（Arc，也称为活动调节基因3.1或Arg3.1）在神经元中被诱导，以响应显著经验和神经活动，并且是活动诱导的突触可塑性形式所必需的，例如长期增强（LTP）和长期抑制（LTD），学习和记忆的细胞基质。Arc最具特征的功能是增强树突棘中AMPA受体的内吞内化，这一过程与LTD有关。Arc也与内体表面淀粉样前体蛋白的蛋白水解加工有关。为了介导这些活性，Arc必须与细胞膜结合，但目前尚不清楚Arc是直接与脂质双分子层结合，还是需要蛋白质-蛋白质相互作用来募集细胞膜。在这项研究中，我们发现Arc在体外与纯磷脂囊泡结合，并在神经元中经历棕榈酰化，这种修饰使其能够直接插入双分子层的疏水核心。棕榈酰化半胱氨酸聚集在一个基序94CLCRC98中，该基序位于蛋白质的n端一半，尚未进行结构表征。与野生型Arc相比，在该基序列中含有三个突变半胱氨酸的Arc的表达不能支持由活性依赖性转录因子MEF2（肌细胞增强因子2）诱导的突触抑制。因此，棕榈酰化似乎至少调节了突触可塑性中Arc功能的一部分。
Activity-regulated cytoskeletal-associated protein (Arc, also known as activity-regulated gene 3.1 or Arg3.1) is induced in neurons in response to salient experience and neural activity and is necessary for activityinduced forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), cellular substrates of learning and memory. The bestcharacterized function of Arc is enhancement of the endocytic internalization of AMPA receptors in dendritic spines, a process associated with LTD. Arc has also been implicated in the proteolytic processing of amyloid precursor protein on the surface of endosomes. To mediate these activities, Arc must associate with cellular membranes, but it is unclear whether Arc binds directly to the lipid bilayer or requires protein–protein interactions for membrane recruitment. In this study, we show that Arc associates with pure phospholipid vesicles in vitro and undergoes palmitoylation in neurons, a modification that allows it to insert directly into the hydrophobic core of the bilayer. The palmitoylated cysteines are clustered in a motif, 94CLCRC98, located in the N-terminal half of the protein, which has not yet been structurally characterized. Expression of Arc with three mutated cysteines in that motif cannot support synaptic depression induced by the activity-dependent transcription factor, MEF2 (myocyte enhancer factor 2), in contrast to wild-type Arc. Thus, it appears that palmitoylation regulates at least a subset of Arc functions in synaptic plasticity.
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影响因子：
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作者：
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DOI：
10.1016/j.bbagen.2015.03.002
发表时间：
2015-06
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
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通讯作者：
Albanesi JP