Positive surface charge of GluN1 N-terminus mediates the direct interaction with EphB2 and NMDAR mobility

• Published in: Nature communications Vol. 11; no. 1; pp. 570 - 16
• Main Authors: Washburn, Halley R., Xia, Nan L., Zhou, Wei, Mao, Yu-Ting, Dalva, Matthew B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/109; 14; 14/19; 38/35; 38/70; 631/378; 631/378/2571/2577; 631/378/2586; 631/378/340; 631/57; 64/86; 82/51; 96; Amino acids; Animals; Antibodies; Binding sites; Biophysics; Cycles; Dendritic plasticity; Dendritic spines; Dendritic Spines - chemistry; Dendritic Spines - genetics; Dendritic Spines - metabolism; Dendritic structure; Density; Domains; Encephalitis; Glutamic acid receptors (ionotropic); Glycosylation; HEK293 Cells; Humanities and Social Sciences; Humans; Ion Channels; Kinases; Ligands; Localization; Mice; Mobility; Models, Molecular; multidisciplinary; N-Methyl-D-aspartic acid receptors; N-Terminus; Nervous System - chemistry; Nervous System - metabolism; Neurons - chemistry; Neurons - metabolism; Neurosciences; Phosphorylation; Polyamines; Postsynaptic density; Protein Conformation; Protein interaction; Protein Interaction Domains and Motifs; Protein-tyrosine kinase receptors; Proteins; Receptor density; Receptor, EphB2 - chemistry; Receptor, EphB2 - genetics; Receptor, EphB2 - metabolism; Receptors; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - metabolism; Retention; Science; Science (multidisciplinary); Spine; Surface charge; Synapses; Synapses - metabolism; Synaptic plasticity; Synaptic transmission; Tyrosine; Tyrosine - chemistry; Tyrosine - metabolism
• DOI: 10.1038/s41467-020-14345-6
• ISSN: 2041-1723

Localization of the N-methyl-D-aspartate type glutamate receptor (NMDAR) to dendritic spines is essential for excitatory synaptic transmission and plasticity. Rather than remaining trapped at synaptic sites, NMDA receptors undergo constant cycling into and out of the postsynaptic density. Receptor movement is constrained by protein-protein interactions with both the intracellular and extracellular domains of the NMDAR. The role of extracellular interactions on the mobility of the NMDAR is poorly understood. Here we demonstrate that the positive surface charge of the hinge region of the N-terminal domain in the GluN1 subunit of the NMDAR is required to maintain NMDARs at dendritic spine synapses and mediates the direct extracellular interaction with a negatively charged phospho-tyrosine on the receptor tyrosine kinase EphB2. Loss of the EphB-NMDAR interaction by either mutating GluN1 or knocking down endogenous EphB2 increases NMDAR mobility. These findings begin to define a mechanism for extracellular interactions mediated by charged domains. NMDA receptors undergo constant cycling into and out of the postsynaptic density. Here authors show that NMDAR's GluN1 subunit is required to maintain NMDARs at dendritic spine synapses by direct extracellular interaction with the receptor tyrosine kinase EphB2.