TY - JOUR
T1 - Bidirectional protein–protein interactions control liquid–liquid phase separation of PSD-95 and its interaction partners
AU - Christensen, Nikolaj Riis
AU - Pedersen, Christian Parsbæk
AU - Sereikaite, Vita
AU - Pedersen, Jannik Nedergaard
AU - Vistrup-Parry, Maria
AU - Sørensen, Andreas Toft
AU - Otzen, Daniel
AU - Teilum, Kaare
AU - Madsen, Kenneth Lindegaard
AU - Strømgaard, Kristian
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Biomolecules
KW - Biophysics
KW - molecular biology
KW - molecular neuroscience
KW - Pharmacology
U2 - 10.1016/j.isci.2022.103808
DO - 10.1016/j.isci.2022.103808
M3 - Journal article
C2 - 35198873
AN - SCOPUS:85124178003
VL - 25
JO - iScience
JF - iScience
SN - 2589-0042
IS - 2
M1 - 103808
ER -