Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs
Summary: 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 in C. elegans. Here, we demonstrate t...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724000226 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dayton J. Goodell |
| collection | DOAJ |
| description | Summary: 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 in C. elegans. Here, we demonstrate that NRAP-1 was sufficient to gate NMDARs and greatly enhanced glutamate-mediated NMDAR gating, thus conferring coincident activation properties to the NMDAR. Intriguingly, vertebrate NMDARs—and chimeric NMDARs where the amino-terminal domain (ATD) of C. elegans NMDARs was replaced by the ATD from vertebrate receptors—were spontaneously active when ectopically expressed in C. elegans neurons. Thus, the ATD is a primary determinant of NRAP-1- and glutamate-mediated gating of NMDARs. We determined the crystal structure of NRAP-1 at 1.9-Å resolution, which revealed two distinct domains positioned around a central low-density lipoprotein receptor class A domain. The NRAP-1 structure, combined with chimeric and mutational analyses, suggests a model where the three NRAP-1 domains work cooperatively to modify the gating of NMDARs. |
| first_indexed | 2024-03-07T19:42:10Z |
| format | Article |
| id | doaj.art-0e71df12b48a4b31bdc42865b9f71de6 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-07T19:42:10Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-0e71df12b48a4b31bdc42865b9f71de62024-02-29T05:18:38ZengElsevierCell Reports2211-12472024-02-01432113694Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARsDayton J. Goodell0Frank G. Whitby1Jerry E. Mellem2Ning Lei3Penelope J. Brockie4Aleksander J. Maricq5Debra M. Eckert6Christopher P. Hill7David M. Madsen8Andres V. Maricq9Department of Neurobiology, University of Utah, Salt Lake City, UT 84112-9458, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112-5650, USADepartment of Neurobiology, University of Utah, Salt Lake City, UT 84112-9458, USADepartment of Neurobiology, University of Utah, Salt Lake City, UT 84112-9458, USADepartment of Neurobiology, University of Utah, Salt Lake City, UT 84112-9458, USASchool of Computing, University of Utah, Salt Lake City, UT 84112, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112-5650, USADepartment of Biochemistry, University of Utah, Salt Lake City, UT 84112-5650, USADepartment of Neurobiology, University of Utah, Salt Lake City, UT 84112-9458, USADepartment of Neurobiology, University of Utah, Salt Lake City, UT 84112-9458, USA; Corresponding authorSummary: 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 in C. elegans. Here, we demonstrate that NRAP-1 was sufficient to gate NMDARs and greatly enhanced glutamate-mediated NMDAR gating, thus conferring coincident activation properties to the NMDAR. Intriguingly, vertebrate NMDARs—and chimeric NMDARs where the amino-terminal domain (ATD) of C. elegans NMDARs was replaced by the ATD from vertebrate receptors—were spontaneously active when ectopically expressed in C. elegans neurons. Thus, the ATD is a primary determinant of NRAP-1- and glutamate-mediated gating of NMDARs. We determined the crystal structure of NRAP-1 at 1.9-Å resolution, which revealed two distinct domains positioned around a central low-density lipoprotein receptor class A domain. The NRAP-1 structure, combined with chimeric and mutational analyses, suggests a model where the three NRAP-1 domains work cooperatively to modify the gating of NMDARs.http://www.sciencedirect.com/science/article/pii/S2211124724000226CP: Molecular biologyCP: Neuroscience |
| spellingShingle | 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 Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs Cell Reports CP: Molecular biology CP: Neuroscience |
| title | Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs |
| title_full | Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs |
| title_fullStr | Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs |
| title_full_unstemmed | Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs |
| title_short | Mechanistic and structural studies reveal NRAP-1-dependent coincident activation of NMDARs |
| title_sort | mechanistic and structural studies reveal nrap 1 dependent coincident activation of nmdars |
| topic | CP: Molecular biology CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724000226 |
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