CASK Regulates SAP97 Conformation and Its Interactions with AMPA and NMDA Receptors
CASK Regulates SAP97 Conformation and Its Interactions with AMPA and NMDA Receptors
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DOI：
10.1523/jneurosci.0816-13.2013
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发表时间：
2013-07-17
影响因子：
5.3
通讯作者：
Green, William N.
中科院分区：
文献类型：
--
作者：
Lin, Eric I.;Jeyifous, Okunola;Green, William N.
SAP97与AMPA受体（AMPARs）和NMDA受体（NMDARs）在突触的分类和运输过程中相互作用。在这里，我们讨论了SAP97如何区分AMPARs和NMDARs，以及接头/支架蛋白CASK在这一过程中起什么作用。利用分子内的SAP97福斯特共振能量转移传感器，我们证明了SAP97在体内处于“扩展”或“紧凑”构象。SAP97的构象是由SAP97和CASK通过各自蛋白上的L27蛋白相互作用域直接相互作用调控的。未结合的SAP97主要呈紧密型构象，而CASK结合将其稳定在扩展构象中。在hek细胞和大鼠海马神经元中，紧密构象中的SAP97优先与含glua1的AMPARs结合和共定位，而扩展构象中的SAP97优先与含glun2b的NMDARs共定位。总之，我们的研究结果提示了CASK结合调节SAP97构象及其随后的ampar和NMDARs在转运到突触过程中的分选和突触靶向的分子机制。
SAP97 interacts with AMPA receptors (AMPARs) and NMDA receptors (NMDARs) during sorting and trafficking to synapses. Here we addressed how SAP97 distinguishes between AMPARs and NMDARs and what role the adaptor/scaffold protein, CASK, plays in the process. Using intramolecular SAP97 Forster resonance energy transfer sensors, we demonstrated that SAP97 is in "extended" or "compact" conformations in vivo. SAP97 conformation was regulated by a direct interaction between SAP97 and CASK through L27 protein-interaction domains on each protein. Unbound SAP97 was mostly in the compact conformation, while CASK binding stabilized it in an extended conformation. InHEKcells and rat hippocampal neurons, SAP97 in the compact conformation preferentially associated and colocalized with GluA1-containing AMPARs, and in the extended conformation colocalized with GluN2B-containing NMDARs. Altogether, our findings suggest a molecular mechanism by which CASK binding regulates SAP97 conformation and its subsequent sorting and synaptic targeting of AMPARs and NMDARs during trafficking to synapses.