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bioRxiv · 10.1101/2021.03.03.433781

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

Christensen, N. R.·Pedersen, C. P.·Sereikaite, V.·Pedersen, J. N.·Vistrup-Parry, M.·Soerensen, A. T.·Otzen, D. E.·Arleth, L.·Teilum, K.·Madsen, K. L.·Stromgaard, K.
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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 post-synapse. Postsynaptic density protein 95 (PSD-95) interacts with a manifold of proteins, including the C-terminal of transmembrane AMPA receptor (AMAPR) regulatory proteins (TARPs). Here, we uncover the minimal essential peptide responsible for the stargazin (TARP-{gamma}2) 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 formation of LLPS. We found that in some cases LLPS formation is dependent on multivalent interactions while in other cases short peptides carrying a high charge 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.

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Christensen, N. R., Pedersen, C. P., Sereikaite, V., Pedersen, J. N., Vistrup-Parry, M., Soerensen, A. T., Otzen, D. E., Arleth, L., Teilum, K., Madsen, K. L., Stromgaard, K.. 2021-03-03. Bi-directional protein-protein interactions control liquid-liquid phase separation of PSD-95 and its interaction partners. https://doi.org/10.1101/2021.03.03.433781

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