Multiphase separation in postsynaptic density regulated by membrane geometry via interaction valency and volume
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Biomolecular condensates are found at various cellular locations, nucleus, cytoplasm, and membrane. These condensates often contain multiple components and can separate into multiple phases with various morphologies such as core-shell droplets, implicating functional roles. Demixing of condensates and their arrangements are determined by competitive interactions and by their locations. Recent studies reported a puzzling multiphase morphology of four components of postsynaptic density: AMPA-receptor, NMDA-receptor, PSD-95, and CaMKII. The multiphase morphology becomes apparently reversed as we move from the solubilized constructs to the membrane. In this study, using this system as a model, we study the multiphase behavior of condensates in solution (3D) and domain formation on and beneath the membrane (2D) and elucidate molecular mechanisms behind the puzzle. Our mesoscopic simulations reproduce that the CaMKII activation induces the core-shell multiphase separation found in 3D in vitro experiment with AMPA-receptor/PSD-95 at the core and NMDA-receptor/CaMKII in the shell. Then, we obtain a reversed morphology on the postsynaptic membrane. The high valency and large volume of CaMKII appears to be a major factor in this reversal. Interestingly, we find that, while the CaMKII has dominant non-specific volume interaction in the 3D system, the specific multivalent interactions overcome the volume interaction for CaMKII beneath the membrane, reversing the morphology. On the membrane, the layered structures of receptors and CaMKIIs reduce the volume effects of CaMKII on receptors, making the multivalent interaction dominant. The membrane domain formation is distinct from the condensate formation in solution and modulated by their layered arrangement.
Significance
Many proteins form condensates in cells, which are often further separated into two or more phases, implicating functional roles. Recent experiments on postsynaptic density proteins provide an interesting puzzle on a multiphasic morphology; while they form core-shell droplets with AMPA-receptor at the core and NMDA receptor in the shell in soluble constructs, the multiphase morphology is reversed when they form nanodomains on the membrane. This study identifies the mechanism behind the puzzle by using computer simulations with a mesoscale model. While active CaMKII, an inducer of the multiphase morphology, has dominant non-specific volume interactions in solution, its specific domain-domain multivalent interaction overcomes the volume interaction under the membrane with their layered arrangement.
