Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs

• DOI: 10.1016/j.celrep.2024.113694
• Publication Date: 2024-01-23T18:20:04Z
• Authors: Dayton J. Goodell; Frank G. Whitby; Jerry E. Mellem; Ning Lei; Penelope J. Brockie; Aleksander J. Maricq; Debra M. Eckert; Christopher P. Hill; David M. Madsen; Andres V. Maricq
• Keywords: 0301 basic medicine; 03 medical and health sciences; QH301-705.5; CP: Neuroscience; CP: Molecular biology; Biology (General); Article

N-methyl-D-aspartate (NMDA)-type ionotropic glutamate receptors have essential roles in neurotransmission and synaptic plasticity. Previously, we identified an evolutionarily conserved protein, NRAP-1, that is required for NMDA receptor (NMDAR) function C. elegans. Here, demonstrate NRAP-1 was sufficient to gate NMDARs greatly enhanced glutamate-mediated NMDAR gating, thus conferring coincident activation properties the NMDAR. Intriguingly, vertebrate NMDARs-and chimeric where amino-terminal domain (ATD) of elegans replaced by ATD from receptors-were spontaneously active when ectopically expressed neurons. Thus, a primary determinant NRAP-1- gating NMDARs. We determined crystal structure at 1.9-Å resolution, which revealed two distinct domains positioned around central low-density lipoprotein class A domain. The structure, combined with mutational analyses, suggests model three work cooperatively modify