The C-terminal domain of zDHHC2 contains distinct sorting signals that regulate intracellular localisation in neurons and neuroendocrine cells.
The C-terminal domain of zDHHC2 contains distinct sorting signals that regulate intracellular localisation in neurons and neuroendocrine cells.
复制标题
DOI：
10.1016/j.mcn.2017.07.007
复制
发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Chamberlain LH
中科院分区：
文献类型：
--
作者：
Salaun C;Ritchie L;Greaves J;Bushell TJ;Chamberlain LH
S-酰基转移酶zDHHC 2介导PSD 95和AKAP 79/150的动态S-酰化，其影响AMPA受体的突触靶向。zDHHC 2对突触活性有反应，并催化在动作电位阻断或应用离子型谷氨酸受体拮抗剂后发生的PSD 95的S-酰化增加。已经提出这些处理通过内体循环途径增加zDHHC 2的质膜递送，从而增强底物可及性。为了更好地理解zDHHC 2的运输以及这可能如何受到神经元活性的调节，我们寻找了调节酶定位的分子内信号。两个信号被映射到zDHHC 2的C-末端尾部：非典型双亮氨酸基序[SxxxLL]和下游NP基序。这些信号的突变增强了zDHHC 2在神经内分泌PC 12细胞和大鼠海马神经元中的质膜积累，与减少的内吞回收一致。此外，这些信号的突变也增加了神经突中酶的积累。有趣的是，几个苏氨酸和丝氨酸残基邻近这些排序基序和磷酸模拟突变体的分析突出了磷酸化在调节这些信号的功效中的潜在作用。这项研究为确定zDHHC 2定位的信号提供了新的分子见解，并强调了调节这些运输信号的潜在机制。zDHHC 2的动态运输调节该S-酰化酶的定位并控制对其底物的获取。在zDHHC 2的C-末端尾内鉴定了两个独立的（和非典型的）序列，其影响酶定位。这些基序的突变诱导zDHHC 2在海马神经元和PC 12细胞的质膜上的积累。磷酸化可能是调节这些分选信号功效的潜在机制。
The S-acyltransferase zDHHC2 mediates dynamic S-acylation of PSD95 and AKAP79/150, which impacts synaptic targeting of AMPA receptors. zDHHC2 is responsive to synaptic activity and catalyses the increased S-acylation of PSD95 that occurs following action potential blockade or application of ionotropic glutamate receptor antagonists. These treatments have been proposed to increase plasma membrane delivery of zDHHC2 via an endosomal cycling pathway, enhancing substrate accessibility. To generate an improved understanding of zDHHC2 trafficking and how this might be regulated by neuronal activity, we searched for intramolecular signals that regulate enzyme localisation. Two signals were mapped to the C-terminal tail of zDHHC2: a non-canonical dileucine motif [SxxxLL] and a downstream NP motif. Mutation of these signals enhanced plasma membrane accumulation of zDHHC2 in both neuroendocrine PC12 cells and rat hippocampal neurons, consistent with reduced endocytic retrieval. Furthermore, mutation of these signals also increased accumulation of the enzyme in neurites. Interestingly, several threonine and serine residues are adjacent to these sorting motifs and analysis of phospho-mimetic mutants highlighted a potential role for phosphorylation in regulating the efficacy of these signals. This study offers new molecular insight into the signals that determine zDHHC2 localisation and highlights a potential mechanism to regulate these trafficking signals. Dynamic trafficking of zDHHC2 regulates the localisation of this S-acylation enzyme and controls access to its substrates. Two separate (and atypical) sequences were identified within the C-terminal tail of zDHHC2 that affect enzyme localisation. Mutating these motifs induced the accumulation of zDHHC2 at the plasma membrane of hippocampal neurons and PC12 cells. Phosphorylation may be a potential mechanism to regulate the efficacy of these sorting signals.
登录
查看更多内容
影响因子：
4.8
作者：
Jensen, Camilla Stampe;Watanabe, Shoji;Misonou, Hiroaki
通讯作者：
Misonou, Hiroaki
影响因子：
16.2
作者：
Hayashi, Takashi;Thomas, Gareth M.;Huganir, Richard L.
通讯作者：
Huganir, Richard L.
影响因子：
4
作者：
Greaves, Jennifer;Chamberlain, Luke H.
通讯作者：
Chamberlain, Luke H.
DOI：
10.1083/jcb.201310021
发表时间：
2014-01-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bonifacino JS
通讯作者：
Bonifacino JS
Kinasephos：用于识别蛋白激酶特异性磷酸化位点的Web工具。
影响因子：
14.9
作者：
Huang, HD;Lee, TY;Tzeng, SW;Horng, JT
通讯作者：
Horng, JT