Gingrich Jeffrey R, Pelkey Kenneth A, Fam Sami R, Huang Yueqiao, Petralia Ronald S, Wenthold Robert J, Salter Michael W
Brain and Behaviour Program, Hospital for Sick Children, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1X8.
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6237-42. doi: 10.1073/pnas.0401413101. Epub 2004 Apr 6.
Src is the prototypic protein tyrosine kinase and is critical for controlling diverse cellular functions. Regions in Src define structural and functional domains conserved in many cell signaling proteins. Src also contains a region of low sequence conservation termed the unique domain, the function of which has until now remained enigmatic. Here, we show that the unique domain of Src is a protein-protein interaction region and we identify NADH dehydrogenase subunit 2 (ND2) as a Src unique domain-interacting protein. ND2 is a subunit of complex I in mitochondria, but we find that ND2 interacts with Src outside this organelle at excitatory synapses in the brain. ND2 acts as an adapter protein anchoring Src to the N-methyl-d-aspartate (NMDA) receptor complex, and is crucial for Src regulation of synaptic NMDA receptor activity. By showing an extramitochondrial action for a protein encoded in the mitochondrial genome, we identify a previously unsuspected means by which mitochondria regulate cellular function, suggesting a new paradigm that may be of general relevance for control of Src signaling.
Src是典型的蛋白酪氨酸激酶，对控制多种细胞功能至关重要。Src中的区域定义了许多细胞信号蛋白中保守的结构和功能域。Src还包含一个序列保守性较低的区域，称为独特结构域，其功能至今仍不清楚。在此，我们表明Src的独特结构域是一个蛋白质-蛋白质相互作用区域，并鉴定出NADH脱氢酶亚基2（ND2）是一种与Src独特结构域相互作用的蛋白质。ND2是线粒体中复合物I的一个亚基，但我们发现ND2在脑内兴奋性突触处的该细胞器外与Src相互作用。ND2作为一种衔接蛋白，将Src锚定到N-甲基-D-天冬氨酸（NMDA）受体复合物上，对Src调节突触NMDA受体活性至关重要。通过展示线粒体基因组编码的一种蛋白质的线粒体外作用，我们确定了一种以前未被怀疑的线粒体调节细胞功能的方式，提示了一种可能与Src信号控制普遍相关的新范式。
