Palmitoylation-dependent CDKL5-PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development
Palmitoylation-dependent CDKL5-PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development
复制标题
棕榈酰化依赖性 CDKL5-PSD-95 相互作用调节 CDKL5 的突触靶向和树突棘发育。
DOI：
10.1073/pnas.1300003110
复制
发表时间：
2013-05-28
影响因子：
11.1
通讯作者：
Xiong, Zhi-Qi
中科院分区：
文献类型：
--
作者：
Zhu, Yong-Chuan;Li, Dan;Xiong, Zhi-Qi
X连锁基因细胞周期蛋白依赖性激酶样5（CDKL 5）在严重的神经发育障碍中发生突变，包括某些形式的非典型Rett综合征，但CDKL 5蛋白在神经元中的功能和调节仍有待阐明。在这里，我们表明，CDKL 5结合到支架蛋白突触后密度（PSD）-95，这种结合促进CDKL 5兴奋性突触的靶向。有趣的是，这种结合不是组成性的，而是由PSD-95上的棕榈酸循环控制的。此外，截短CDKL 5的C末端尾部的致病突变减少了其与PSD-95的结合和突触积累。重要的是，通过RNA干扰（RNAi）或干扰CDKL 5-PSD-95相互作用下调CDKL 5抑制树突棘形成和生长。这些结果表明棕榈酰化依赖性CDKL 5-PSD-95相互作用在将CDKL 5定位于正常脊柱发育的突触中起关键作用，并表明致病性突变对这种相互作用的破坏可能与CDKL 5相关疾病的发病机制有关。
The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in severe neurodevelopmental disorders, including some forms of atypical Rett syndrome, but the function and regulation of CDKL5 protein in neurons remain to be elucidated. Here, we show that CDKL5 binds to the scaffolding protein postsynaptic density (PSD)-95, and that this binding promotes the targeting of CDKL5 to excitatory synapses. Interestingly, this binding is not constitutive, but governed by palmitate cycling on PSD-95. Furthermore, pathogenic mutations that truncate the C-terminal tail of CDKL5 diminish its binding to PSD-95 and synaptic accumulation. Importantly, down-regulation of CDKL5 by RNA interference (RNAi) or interference with the CDKL5-PSD-95 interaction inhibits dendritic spine formation and growth. These results demonstrate a critical role of the palmitoylation- dependent CDKL5-PSD-95 interaction in localizing CDKL5 to synapses for normal spine development and suggest that disruption of this interaction by pathogenic mutationsmay be implicated in the pathogenesis of CDKL5-related disorders.