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

Zheng Shen, Daxiao Sun, Adriana Savastano, Sára Joana Varga, Maria-Sol Cima-Omori, Stefan Becker, Alf Honigmann and Markus Zweckstetter ()
Additional contact information
Zheng Shen: German Center for Neurodegenerative Diseases (DZNE)
Daxiao Sun: Max Planck Institute of Molecular Cell Biology and Genetics
Adriana Savastano: German Center for Neurodegenerative Diseases (DZNE)
Sára Joana Varga: German Center for Neurodegenerative Diseases (DZNE)
Maria-Sol Cima-Omori: German Center for Neurodegenerative Diseases (DZNE)
Stefan Becker: Department of NMR-based Structural Biology
Alf Honigmann: Max Planck Institute of Molecular Cell Biology and Genetics
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-42295-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42295-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-42295-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().