Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density

• Published in: Nature communications Vol. 14; no. 1; p. 6839
• Main Authors: Shen, Zheng, Sun, Daxiao, Savastano, Adriana, Varga, Sára Joana, Cima-Omori, Maria-Sol, Becker, Stefan, Honigmann, Alf, Zweckstetter, Markus
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.10.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378/1689/1283; 631/535/878/1263; 82/6; Alzheimer's disease; Amino acids; Binding; C-Terminus; Clusters; Cognitive ability; Condensates; Density; Glutamate receptors; Glutamic acid receptors (ionotropic); Guanylate kinase; Humanities and Social Sciences; Impairment; Kinases; Localization; Memory; Mimicry; Molecular modelling; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neurodegenerative diseases; Postsynapse; Postsynaptic density; Postsynaptic density proteins; Proteins; Receptors; Science; Science (multidisciplinary); Tau protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-42295-2

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. Cognitive impairment in Alzheimer’s disease is associated with Tau at the postsynapse. We show that multivalent Tau interactions arrest in vitro condensates and clusters mimicking the postsynaptic density that may result in synaptic dysfunction.