Identification of an Atypical Calcium-Dependent Calmodulin Binding Site on the C-terminal domain of GluN2A Public Deposited

http://ir.library.oregonstate.edu/concern/articles/n009w399n

This is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier and can be found at: http://www.journals.elsevier.com/biochemical-and-biophysical-research-communications/

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  • N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion channels assembled from four subunits that each have a common membrane topology. The intracellular carboxyl terminal domain (CTD) of each subunit varies in length, is least conserved between subunits, and binds multiple intracellular proteins. We defined a region of interest in the GluN2A CTD, downstream of well-characterized membraneproximal motifs, that shares only 29% sequence similarity with the equivalent region of GluN2B. GluN2A (amino acids 875-1029) was fused to GST and used as a bait to identify proteins from mouse brain with the potential to bind GluN2A as a function of calcium. Using mass spectrometry we identified calmodulin as a calcium-dependent GluN2A binding partner. Equilibrium fluorescence spectroscopy experiments indicate that Ca²⁺/calmodulin binds GluN2A with high affinity (5.2 ± 2.4 nM) in vitro. Direct interaction of Ca²⁺/calmodulin with GluN2A was not affected by disruption of classic sequence motifs associated with Ca²⁺/calmodulin target recognition, but was critically dependent upon Trp-1014. These findings provide new insight into the potential of Ca²⁺/calmodulin, previously considered a GluN1-binding partner, to influence NMDA receptors by direct association.
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  • Bajaj, G., Hau, A. M., Hsu, P., Gafken, P. R., Schimerlik, M. I., & Ishmael, J. E. (2014). Identification of an atypical calcium-dependent calmodulin binding site on the C-terminal domain of GluN2A. Biochemical and Biophysical Research Communications, 444(4), 588-594. doi:10.1016/j.bbrc.2014.01.111
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