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Bidirectional protein-protein interactions control liquid-liquid phase separation of PSD-95 and its interaction partners

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  • Nikolaj Riis Christensen, University of Copenhagen
  • ,
  • Christian Parsbæk Pedersen, University of Copenhagen
  • ,
  • Vita Sereikaite, University of Copenhagen
  • ,
  • Jannik Nedergaard Pedersen
  • ,
  • Maria Vistrup-Parry, University of Copenhagen
  • ,
  • Andreas Toft Sørensen, University of Copenhagen
  • ,
  • Daniel Otzen
  • Kaare Teilum, University of Copenhagen
  • ,
  • Kenneth Lindegaard Madsen, University of Copenhagen
  • ,
  • Kristian Strømgaard, University of Copenhagen

The organization of the postsynaptic density (PSD), a protein-dense semi-membraneless organelle, is mediated by numerous specific protein-protein interactions (PPIs) which constitute a functional postsynapse. The PSD protein 95 (PSD-95) interacts with a manifold of proteins, including the C-terminal of transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs). Here, we uncover the minimal essential peptide responsible for the Stargazin (TARP-γ2)-mediated liquid-liquid phase separation (LLPS) formation of PSD-95 and other key protein constituents of the PSD. Furthermore, we find that pharmacological inhibitors of PSD-95 can facilitate the formation of LLPS. We found that in some cases LLPS formation is dependent on multivalent interactions, while in other cases short, highly charged peptides are sufficient to promote LLPS in complex systems. This study offers a new perspective on PSD-95 interactions and their role in LLPS formation, while also considering the role of affinity over multivalency in LLPS systems.

Original languageEnglish
Article number103808
Number of pages26
Publication statusPublished - Feb 2022

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