Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
| Autor: | Nathaniel Stanley, Vijay S. Pande, Anton V. Sinitskiy, Jesse E. Hanson, Benjamin D. Sellers, David H. Hackos |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Protein Conformation
alpha-Helical 0301 basic medicine Glycan Glycosylation Patch-Clamp Techniques Glycine Gene Expression Nerve Tissue Proteins Molecular Dynamics Simulation medicine.disease_cause Receptors N-Methyl-D-Aspartate Article Xenopus laevis 03 medical and health sciences chemistry.chemical_compound Polysaccharides medicine Animals Humans Protein Interaction Domains and Motifs Receptor chemistry.chemical_classification Mutation Binding Sites Multidisciplinary biology Biomolecules (q-bio.BM) Potentiator Recombinant Proteins carbohydrates (lipids) Kinetics 030104 developmental biology Biochemistry chemistry nervous system Quantitative Biology - Biomolecules FOS: Biological sciences Oocytes biology.protein Biophysics Thermodynamics NMDA receptor Protein Conformation beta-Strand Glycoprotein Protein Binding |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep44578 |
| Popis: | N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extensive molecular dynamics simulations of GluN1 and GluN2B ligand binding domains (LBDs) of NMDARs to investigate these effects. Our simulations predict that intra-domain interactions involving the glycan attached to residue GluN1-N440 stabilize closed-clamshell conformations of the GluN1 LBD. The glycan on GluN2B-N688 shows a similar, though weaker, effect. Based on these results, and assuming the transferability of the results of LBD simulations to the full receptor, we predict that glycans at GluN1-N440 might play a potentiator role in NMDARs. To validate this prediction, we perform electrophysiological analysis of full-length NMDARs with a glycosylation-preventing GluN1-N440Q mutation, and demonstrate an increase in the glycine EC50 value. Overall, our results suggest an intramolecular potentiating role of glycans on NMDA receptors. |
| Databáze: | OpenAIRE |
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