An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90
An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90
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DOI：
10.1523/jneurosci.20-10-03580.2000
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发表时间：
2000-05-15
影响因子：
5.3
通讯作者：
Sheng, M
中科院分区：
文献类型：
--
作者：
Shin, HW;Hsueh, YP;Sheng, M
膜相关鸟苷酸激酶（MAGUK）蛋白质的突触后密度-95（PSD-95）/SAP 90家族的成员作为在神经元突触处组织蛋白质信号传导复合物的多模块支架起作用。MAGUK蛋白含有PDZ、Src同源性3（SH 3）和鸟苷酸激酶（GK）样结构域，所有这些结构域都可以作为特异性蛋白质-蛋白质相互作用的位点。我们在这里报告了MAGUKs的PSD-95家族中SH 3结构域和GK区域之间的直接蛋白质-蛋白质相互作用。PSD-95家族的SH 3结构域似乎具有非典型的结合特异性，因为经典的SH 3结合（-P-X-X-P-）基序在GK结构域中不存在。尽管SH 3-GK结合可以分子内或分子间方式发生，但分子内模式是优选的，这可能是因为当SH 3和GK结构域在同一多肽中相邻时，可获得额外的三级相互作用。破坏分子内SH 3-GK相互作用的突变不干扰PSD-95与K+通道Kv1.4或GK结构域结合蛋白GKAP的结合。然而，相同的突变，抑制PSD-95的Kv1.4的聚类，这表明分子内SH 3-GK相互作用可以调节PSD-95的聚类活性。
Members of the postsynaptic density-95 (PSD-95)/SAP90 family of membrane-associated guanylate kinase (MAGUK) proteins function as multimodular scaffolds that organize protein-signaling complexes at neuronal synapses. MAGUK proteins contain PDZ, Src homology 3 (SH3), and guanylate kinase (GK)-like domains, all of which can function as sites for specific protein-protein interactions. We report here a direct protein-protein interaction between the SH3 domain and the GK region in the PSD-95 family of MAGUKs. The SH3 domain of the PSD-95 family appears to have an atypical binding specificity, because the classical SH3 binding (-P-X-X-P-) motif is absent from the GK domain. Although SH3-GK binding can occur in either an intramolecular or intermolecular manner, the intramolecular mode is preferred, possibly because of additional tertiary interactions available when the SH3 and GK domains are adjacent in the same polypeptide. Mutations disrupting the intramolecular SH3-GK interaction do not interfere with PSD-95 association with the K+ channel Kv1.4 or with the GK domain-binding protein GKAP. The same mutations, however, inhibit the clustering of Kv1.4 by PSD-95, suggesting that the intramolecular SH3-GK interaction may modulate the clustering activity of PSD-95.