An evolutionary switch in ND2 enables Src kinase regulation of NMDA receptors
| Autor: | Yi Na Dong, Wen-Bo Zhang, Mickael Krzeminski, Alaji Bah, Michael W. Salter, Heather Leduc-Pessah, Julie D. Forman-Kay, David P. Scanlon |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Science Protein subunit Primary Cell Culture Protein domain General Physics and Astronomy Hippocampus Receptors N-Methyl-D-Aspartate Article General Biochemistry Genetics and Molecular Biology Evolution Molecular 03 medical and health sciences Protein Domains mental disorders Animals Humans Homology modeling Phosphorylation Rats Wistar Neurons Electron Transport Complex I Multidisciplinary Sequence Homology Amino Acid Chemistry musculoskeletal neural and ocular physiology Signal transducing adaptor protein NADH Dehydrogenase General Chemistry Rats Up-Regulation Cell biology Transmembrane domain HEK293 Cells src-Family Kinases 030104 developmental biology nervous system Female biological phenomena cell phenomena and immunity Tyrosine kinase Software psychological phenomena and processes Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-14 (2017) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/ncomms15220 |
| Popis: | 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. N-methyl D-aspartate receptor (NMDAR) activity is modulated by Src tyrosine kinase via the mitochondrial protein NADH dehydrogenase subunit 2 (ND2). Here the authors show that ND2 interacts with the transmembrane region of NMDAR GluN1 subunit, a process that is crucial for Src regulation of NMDAR activity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|