Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density.
Nat Commun
; 14(1): 6839, 2023 10 27.
Article
em En
| MEDLINE
| ID: mdl-37891164
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos e Proteínas de Sinalização Intracelular
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article