Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
Abstract
Alzheimer’s disease begins with mild memory loss and slowly destroys memory and thinking. Cognitive impairment in Alzheimer’s disease has been associated with the localization of the microtubule-associated protein Tau at the postsynapse. However, the correlation between Tau at the postsynapse and synaptic dysfunction remains unclear. Here, we show that Tau arrests liquid-like droplets formed by the four postsynaptic density proteins PSD-95, GKAP, Shank, Homer in solution, as well as NMDA (N-methyl-D-aspartate)-receptor-associated protein clusters on synthetic membranes. Tau-mediated condensate/cluster arrest critically depends on the binding of multiple interaction motifs of Tau to a canonical GMP-binding pocket in the guanylate kinase domain of PSD-95. We further reveal that competitive binding of a high-affinity phosphorylated peptide to PSD-95 rescues the diffusional dynamics of an NMDA truncated construct, which contains the last five amino acids of the NMDA receptor subunit NR2B fused to the C-terminus of the tetrameric GCN4 coiled-coil domain, in postsynaptic density-like condensates/clusters. Taken together, our findings propose a molecular mechanism where Tau modulates the dynamic properties of the postsynaptic density.
Details
Original language | English |
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Article number | 6839 |
Journal | Nature communications |
Volume | 14 |
Publication status | Published - 27 Oct 2023 |
Peer-reviewed | Yes |
External IDs
Scopus | 85174830049 |
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PubMed | 37891164 |
Keywords
Keywords
- Humans, Intracellular Signaling Peptides and Proteins/metabolism, Nerve Tissue Proteins/metabolism, Post-Synaptic Density/metabolism, Alzheimer Disease, N-Methylaspartate, Membrane Proteins/metabolism, Disks Large Homolog 4 Protein/metabolism, Receptors, N-Methyl-D-Aspartate/metabolism