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

ABSTRACT: 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.

SUBMITTER: Christensen NR

PROVIDER: S-EPMC8844826 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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

Christensen Nikolaj Riis NR Pedersen Christian Parsbæk CP Sereikaite Vita V Pedersen Jannik Nedergaard JN Vistrup-Parry Maria M Sørensen Andreas Toft AT Otzen Daniel D Teilum Kaare K Madsen Kenneth Lindegaard KL Strømgaard Kristian K

iScience 20220125 2

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 (LLP ...[more]

PMID: 35198873

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Dataset Information

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

Publications

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

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