PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain
PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain
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DOI：
10.1074/jbc.274.39.27467
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发表时间：
1999-09-24
影响因子：
4.8
通讯作者：
Bredt, DS
中科院分区：
文献类型：
--
作者：
Christopherson, KS;Hillier, BJ;Bredt, DS
小脑中一氧化氮（NO）的生物合成优先被N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体的钙内流激活，表明这些受体与神经元型NO合酶（nNOS）之间存在特异性联系。在这里，我们发现，PSD-95组装一个突触后蛋白复合物含有nNOS和NMDA受体。该复合物的形成由PSD-95的PDZ结构域介导，其结合到特定NMDA受体亚基的COOH末端。相比之下，nNOS通过一种新的PDZ-PDZ相互作用被募集到该复合物中，其中PSD-95识别与共有nNOS PDZ结构域相邻的内部基序。该内部基序是nNOS PDZ的结构化“假肽”延伸，其与PSD-95 PDZ 2的肽结合口袋相互作用。这种不对称相互作用使得nNOS PDZ结构域的肽结合口袋可用于与另外的COOH末端PDZ配体相互作用。因此，我们发现nNOS PDZ结构域可以同时结合PSD-95 PDZ 2和COOH末端肽。nNOS PDZ结构域的这种二价性质进一步扩大了通过PDZ结构域组装蛋白质网络的范围。
Nitric oxide (NO) biosynthesis in cerebellum is preferentially activated by calcium influx through N-methyl-D-aspartate (NMDA)-type glutamate receptors, suggesting that there is a specific link between these receptors and neuronal NO synthase (nNOS). Here, we find that PSD-95 assembles a postsynaptic protein complex containing nNOS and NMDA receptors. Formation of this complex is mediated by the PDZ domains of PSD-95, which bind to the COOH termini of specific NMDA receptor subunits. In contrast, nNOS is recruited to this complex by a novel PDZ-PDZ interaction in which PSD-95 recognizes an internal motif adjacent to the consensus nNOS PDZ domain. This internal motif is a structured "pseudo-peptide" extension of the nNOS PDZ that interacts with the peptide-binding pocket of PSD-95 PDZ2. This asymmetric interaction leaves the peptide-binding pocket of the nNOS PDZ domain available to interact with additional COOH-terminal PDZ ligands. Accordingly, we find that the nNOS PDZ domain can bind PSD-95 PDZ2 and a COOH-terminal peptide simultaneously. This bivalent nature of the nNOS PDZ domain further expands the scope for assembly of protein networks by PDZ domains.