Kalia Lorraine V, Pitcher Graham M, Pelkey Kenneth A, Salter Michael W
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
EMBO J. 2006 Oct 18;25(20):4971-82. doi: 10.1038/sj.emboj.7601342. Epub 2006 Sep 21.
The tyrosine kinase Src upregulates the activity of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) and tyrosine phosphorylation of this receptor is critical for induction of NMDAR-dependent plasticity of synaptic transmission. A binding partner for Src within the NMDAR complex is the protein PSD-95. Here we demonstrate an interaction of PSD-95 with Src that does not require the well-characterized domains of PSD-95. Rather, we show binding to Src through a 12-amino-acid sequence in the N-terminal region of PSD-95, a region not previously known to participate in protein-protein interactions. This region interacts directly with the Src SH2 domain. Contrary to typical SH2 domain binding, the PSD-95-Src SH2 domain interaction is phosphotyrosine-independent. Binding of the Src-interacting region of PSD-95 inhibits Src kinase activity and reduces NMDAR phosphorylation. Intracellularly administering a peptide matching the Src SH2 domain-interacting region of PSD-95 depresses NMDAR currents in cultured neurons and inhibits induction of long-term potentiation in hippocampus. Thus, the PSD-95-Src SH2 domain interaction suppresses Src-mediated NMDAR upregulation, a finding that may be of broad importance for synaptic transmission and plasticity.
酪氨酸激酶Src上调谷氨酸受体（NMDAR）的N-甲基-D-天冬氨酸亚型的活性，并且该受体的酪氨酸磷酸化对于诱导NMDAR依赖性突触传递可塑性至关重要。NMDAR复合物中Src的一个结合伴侣是蛋白PSD-95。在此我们证明了PSD-95与Src之间的相互作用，这种相互作用并不需要PSD-95中那些已被充分表征的结构域。相反，我们发现PSD-95通过其N端区域的一个12个氨基酸的序列与Src结合，该区域以前并不被认为参与蛋白质-蛋白质相互作用。这个区域直接与Src的SH2结构域相互作用。与典型的SH2结构域结合不同，PSD-95与Src的SH2结构域相互作用不依赖于磷酸酪氨酸。PSD-95的Src相互作用区域的结合会抑制Src激酶活性并减少NMDAR的磷酸化。在细胞内给予与PSD-95的Src SH2结构域相互作用区域匹配的肽会抑制培养神经元中的NMDAR电流，并抑制海马体中长时程增强的诱导。因此，PSD-95与Src的SH2结构域相互作用抑制了Src介导的NMDAR上调，这一发现可能对突触传递和可塑性具有广泛的重要意义。
