Clustering and synaptic targeting of PICK1 requires direct interaction between the PDZ domain and lipid membranes
Clustering and synaptic targeting of PICK1 requires direct interaction between the PDZ domain and lipid membranes
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DOI：
10.1038/sj.emboj.7601860
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发表时间：
2007-10-31
期刊：
影响因子：
11.4
通讯作者：
Zhang, Mingjie
中科院分区：
文献类型：
--
作者：
Pan, Lifeng;Wu, Hao;Zhang, Mingjie
(P)在bar下蛋白（i）在bar下与（c k）在bar下相互作用在bar下酶（1）在bar下（PICK 1）调节受体和离子通道如AMPA受体的运输。传统上，PICK 1 PDZ结构域被认为是能够与PICK 1转运的受体结合的接头，而脂质结合BAR结构域的功能是将PICK 1直接拴系到膜上。在这里，我们表明PICK 1 PDZ结构域可以直接与脂质膜相互作用。PDZ结构域和脂质膜的相互作用是由一个多元氨基酸簇和一个保守的'Cys-Pro-Cys'基序位于远离肽配体结合沟介导的。PDZ和脂质膜相互作用的破坏完全取消了PICK 1的突触靶向。虽然CPC基序的突变不影响PICK 1和AMPA受体之间的相互作用，但突变的PICK 1不能聚集受体的GluR 2亚基。在神经元中，含有相同突变的PICK 1在AMPA受体的运输中显示出显着受损的能力。总之，我们的研究结果不仅揭示了PICK 1 PDZ结构域的新的脂质膜结合特性，而且还提供了支持PDZ-脂质相互作用的功能相关性的直接证据。
(P) under bar rotein (i) under bar nteracting with (c k) under bar inase (1) under bar (PICK1) regulates the trafficking of receptors and ion-channels such as AMPA receptors. Traditionally, the PICK1 PDZ domain is regarded as an adaptor capable of binding to receptors trafficked by PICK1, and the lipid-binding BAR domain functions to tether PICK1 directly to membranes. Here, we show that the PICK1 PDZ domain can directly interact with lipid membranes. The PDZ domain and lipid membrane interaction is mediated by both a polybasic aminoacid cluster and a conserved 'Cys-Pro-Cys' motif located away from the peptide ligand-binding groove. Disruption of the PDZ and lipid membrane interaction totally abolished synaptic targeting of PICK1. Although mutation of the CPC motif did not affect the interaction between PICK1 and AMPA receptors, the mutant PICK1 was unable to cluster the GluR2 subunit of the receptor. In neurons, PICK1 containing the same mutation displayed dramatically compromised capacity in the trafficking of AMPA receptors. Taken together, our findings not only uncovered the novel lipid membrane-binding property of the PICK1 PDZ domain, but also provided direct evidence supporting the functional relevance of the PDZ-lipid interaction.