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Multivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density.
Shen, Zheng; Sun, Daxiao; Savastano, Adriana; Varga, Sára Joana; Cima-Omori, Maria-Sol; Becker, Stefan; Honigmann, Alf; Zweckstetter, Markus.
Afiliação
  • Shen Z; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
  • Sun D; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
  • Savastano A; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
  • Varga SJ; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
  • Cima-Omori MS; German Center for Neurodegenerative Diseases (DZNE), Von-Siebold-Str. 3a, 37075, Göttingen, Germany.
  • Becker S; Max Planck Institute for Multidisciplinary Sciences, Department of NMR-based Structural Biology, Am Fassberg 11, 37077, Göttingen, Germany.
  • Honigmann A; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
  • Zweckstetter M; Technische Universität Dresden, Biotechnologisches Zentrum (BIOTEC), Dresden, Germany.
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.
Assuntos

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

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