Unique Domain Anchoring of Src to Synaptic NMDA Receptors via the Mitochondrial Protein NADH Dehydrogenase Subunit 2

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-04, Vol.101 (16), p.6237-6242
Main Authors: Gingrich, Jeffrey R., Pelkey, Kenneth A., Fam, Sami R., Huang, Yueqiao, Petralia, Ronald S., Wenthold, Robert J., Salter, Michael W., Siekevitz, Philip
Format: Article
Language:English
Subjects:
Amino acids
Animals
Antibodies
Biological Sciences
Cells, Cultured
Central nervous system
Complementary DNA
Enzymes
Hippocampus - cytology
Hippocampus - enzymology
Hippocampus - metabolism
Humans
Mice
Mitochondria
Mitochondria - metabolism
NADH Dehydrogenase - metabolism
Neurology
Neurons
Physiological regulation
Proteins
Rats
Receptors
Receptors, N-Methyl-D-Aspartate - metabolism
src-Family Kinases - metabolism
Synapses
Yeasts
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0401413101