An evolutionary switch in ND2 enables Src kinase regulation of NMDA receptors

David P. Scanlon, Alaji Bah, Mickaël Krzeminski, Wenbo Zhang, Heather L. Leduc-Pessah, Yi Na Dong, Julie D. Forman-Kay () and Michael W. Salter ()
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David P. Scanlon: Program in Neurosciences & Mental Health, The Hospital for Sick Children
Alaji Bah: Program in Molecular Medicine, The Hospital for Sick Children
Mickaël Krzeminski: Program in Molecular Medicine, The Hospital for Sick Children
Wenbo Zhang: Program in Neurosciences & Mental Health, The Hospital for Sick Children
Heather L. Leduc-Pessah: Program in Neurosciences & Mental Health, The Hospital for Sick Children
Yi Na Dong: Program in Neurosciences & Mental Health, The Hospital for Sick Children
Julie D. Forman-Kay: Program in Molecular Medicine, The Hospital for Sick Children
Michael W. Salter: Program in Neurosciences & Mental Health, The Hospital for Sick Children

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract The non-receptor tyrosine kinase Src is a key signalling hub for upregulating the function of N-methyl D-aspartate receptors (NMDARs). Src is anchored within the NMDAR complex via NADH dehydrogenase subunit 2 (ND2), a mitochondrially encoded adaptor protein. The interacting regions between Src and ND2 have been broadly identified, but the interaction between ND2 and the NMDAR has remained elusive. Here we generate a homology model of ND2 and dock it onto the NMDAR via the transmembrane domain of GluN1. This interaction is enabled by the evolutionary loss of three helices in bilaterian ND2 proteins compared to their ancestral homologues. We experimentally validate our model and demonstrate that blocking this interaction with an ND2 fragment identified in our experimental studies prevents Src-mediated upregulation of NMDAR currents in neurons. Our findings establish the mode of interaction between an NMDAR accessory protein with one of the core subunits of the receptor.

Date: 2017
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DOI: 10.1038/ncomms15220

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