Interaction between the guanylate kinase domain of PSD-95 and the proline-rich region and microtubule binding repeats 2 and 3 of tau

Emmanuel Prikas, Holly Ahel, Kristie Stefanoska, Prita Riana Asih, Alexander Volkerling, Lars M. Ittner, Arne Ittner

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The microtubule-associated protein tau is a key factor in neurodegenerative proteinopathies and is predominantly found in the neuronal axon. However, somatodendritic localization of tau occurs for a subset of pathological and physiologic tau. Dendritic tau can localize to post-synapses where it interacts with proteins of the post-synaptic density (PSD) protein PSD-95, a membrane-associated guanylate kinase (MAGUK) scaffold factor for organization of protein complexes within the PSD, to mediate downstream signals. The sub-molecular details of this interaction, however, remain unclear. Here, we use interaction mapping in cultured cells to demonstrate that tau interacts with the guanylate kinase (GUK) domain in the C-terminal region of PSD-95. The PSD-95 GUK domain is required and sufficient for a complex with full-length human tau. Mapping the interaction of the MAGUK core on tau revealed the microtubule binding repeats 2 and 3 and the proline-rich region contribute to this interaction, while the N- and C-terminal regions of tau inhibit interaction. These results reveal intramolecular determinants of the protein complex of tau and PSD-95 and increase our understanding of tau interactions regulating neurotoxic signaling at the molecular level.
Original languageEnglish
Pages (from-to)606-616
Number of pages11
JournalBiochemistry and Cell Biology
Volume99
Issue number5
Early online date1 Apr 2021
DOIs
Publication statusPublished - Sep 2021

Keywords

  • microtubule-associated protein tau
  • membrane-associated guanylate kinase
  • MAGUK
  • PSD-95
  • interaction
  • protein complex
  • binding site
  • interaction mapping

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