Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks
Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks
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DOI：
10.1242/jcs.00617
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发表时间：
2003-08-01
影响因子：
4
通讯作者：
Bredt, DS
中科院分区：
文献类型：
--
作者：
Christopherson, KS;Sweeney, NT;Bredt, DS
突触后密度蛋白95（PSD-95/SAP-90）是棕榈酰化的。一种膜相关鸟苷酸激酶，可寡聚化和聚集脑内兴奋性突触处的离子通道和相关信号机制。然而，PSD-95寡聚化的机制及其与离子通道聚集的关系仍然不确定。在这里，我们发现PSD-95的多聚化仅由其前13个氨基酸决定，这也具有显著的异源蛋白寡聚化能力。多聚化不涉及共价键，而是13个氨基酸基序中两个半胱氨酸残基的棕榈酰化。这种脂质介导的寡聚化是PSD-95基序的一种特定性质，因为它在其他棕榈酰化结构域中未观察到。聚集K+通道Kv1.4需要棕榈酰化PSD-95与四聚体K+通道亚基的相互作用，但令人惊讶的是，不需要PSD-95的多聚化。最后，用2-溴棕榈酸酯破坏棕榈酰化分散PSD-95/K+通道簇。这些数据表明，新的模型K+通道聚簇PSD-95-蛋白质棕榈酰化调控的可逆过程。
Postsynaptic density protein 95 (PSD-95/SAP-90) is a palmitoylated. membrane-associated guanylate kinase that oligomerizes and clusters ion channels and associated signaling machinery at excitatory synapses in brain. However, the mechanism for PSD-95 oligomerization and its relationship to ion channel clustering remain uncertain. Here, we find that multimerization of PSD-95 is determined by only its first 13 amino acids, which also have a remarkable capacity to oligomerize heterologous proteins. Multimerization does not involve a covalent linkage but rather palmitoylation of two cysteine residues in the 13 amino acid motif. This lipid-mediated oligomerization is a specific property of the PSD-95 motif, because it is not observed with other palmitoylated domains. Clustering K+ channel Kv1.4 requires interaction of palmitoylated PSD-95 with tetrameric K+ channel subunits but, surprisingly, does not require multimerization of PSD-95. Finally, disrupting palmitoylation with 2-bromopalmitate disperses PSD-95/K+-channel clusters. These data suggest new models for K+ channel clustering by PSD-95-a reversible process regulated by protein palmitoylation.