Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development
| Autor: | Jing Zheng, Dan Li, Bin Lu, Shilin Zhao, Rong Zeng, Yong-Chuan Zhu, Zhi-Qi Xiong, Lu Wang |
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| Rok vydání: | 2013 |
| Předmět: |
Scaffold protein
Dendritic spine Dendritic Spines Lipoylation CDKL5 Protein Serine-Threonine Kinases Biology Hippocampus Rats Sprague-Dawley Palmitoylation RNA interference mental disorders Animals Immunoprecipitation Cells Cultured Neurons Multidisciplinary Intracellular Signaling Peptides and Proteins Membrane Proteins Biological Sciences Rats Cell biology nervous system Disks Large Homolog 4 Protein Mutation Synapses Excitatory postsynaptic potential Electrophoresis Polyacrylamide Gel RNA Interference Postsynaptic density |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:9118-9123 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1300003110 |
| Popis: | 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 mutations may be implicated in the pathogenesis of CDKL5-related disorders. |
| Databáze: | OpenAIRE |
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