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Phase Separation-Mediated TARP/MAGUK Complex Condensation and AMPA Receptor Synaptic Transmission

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Zeng, Menglong, Díaz-Alonso, Javier, Ye, Fei, Chen, Xudong, Xu, Jia, Ji, Zeyang, Nicoll, Roger A., Zhang, Mingjie·2019·Neuron
DOI 10.1016/j.neuron.2019.08.001PMC PMC6842113
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Abstract

Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) modulate AMPAR synaptic trafficking and transmission via disc-large (DLG) subfamily of membrane-associated guanylate kinases (MAGUKs). Despite extensive studies, the molecular mechanism governing specific TARP/MAGUK interaction remains elusive. Using stargazin and PSD-95 as the representatives, we discover that the entire tail of stargazin (Stg_CT) is required for binding to PSD-95. The PDZ binding motif (PBM) and an Arg-rich motif upstream of PBM conserved in TARPs bind to multiple sites on PSD-95, thus resulting in a highly specific and multivalent stargazin/PSD-95 complex. Stargazin in complex with PSD-95 or PSD-95-assembled postsynaptic complexes form highly concentrated and dynamic condensates via phase separation, reminiscent of stargazin/PSD-95-mediated AMPAR synaptic clustering and trapping. Importantly, charge neutralization mutations in TARP_CT Arg-rich motif weakened TARP's condensation with PSD-95 and impaired TARP-mediated AMPAR synaptic transmission in mice hippocampal neurons. The TARP_CT/PSD-95 interaction mode may have implications for understanding clustering of other synaptic transmembrane proteins.

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  • Phosphomimic mutations of TARP serines greatly diminish both binding of the TARP CTD to PSD-95 and rescue of AMPAR transmission in AMPAR-deleted cells.

    “Phosphomimic mutations greatly diminished both the binding of the TARP CTD to PSD-95 and the rescue of AMPAR transmission in AMPAR-deleted cells.”

    From Synaptic memory and CaMKII (2023) · cites this paper as [289]

  • Delivery of AMPARs to synapses requires binding of TARPs via their PDZ binding motifs to PSD-95.

    “It is now well established that the delivery of AMPARs to synapses requires the binding of TARPs, via their PDZ binding motifs (PBMs), to PSD-95 (278, 279, 286, 289, 294).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [289]

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Cited by

Sorted by citations

Authors
Zeng, M., Díaz-Alonso, J., Ye, F., Chen, X., Xu, J., Ji, Z., Nicoll, R. A., & Zhang, M.
Affiliations
  • Hong Kong University of Science and Technology (HK)
  • University of California, San Francisco (US)
Corresponding author
Zhang, Mingjie
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2019-11
Volume
104
Issue
3
Pages
529-543.e6
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2019.08.001
PMC
PMC6842113
OpenAlex
W2971667181
Cited by
171
References
15
Citations by year
2026: 17 · 2025: 35 · 2024: 26 · 2023: 20 · 2022: 22 · 2021: 30 · 2020: 20 · 2019: 1
FWCI
8.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • Ministry of Science and Technology of the People's Republic of China (2014CB910204)
  • Research Grants Council, University Grants Committee
  • National Institutes of Health (MH118425)
  • Institute of Advanced Studies, University of Bristol
  • Hong Kong University of Science and Technology
  • China Association for Science and Technology
  • Glaucoma Research Foundation
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
stargazin, PSD-95, TARP, AMPA receptors, phase separation, PDZ-binding motif, synaptic transmission, hippocampal neurons
MeSH terms
Disks Large Homolog 4 Protein, Animals, Hippocampus, Synaptic Transmission, Neurons, Calcium Channels, Receptors, AMPA, Protein Transport, Mice, Guanylate Kinases, Post-Synaptic Density

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