Assembly of Model Postsynaptic Densities Involves Interactions Auxiliary to Stoichiometric Binding
arXiv:2110.02937 · doi:10.1016/j.bpj.2021.10.008
Abstract
The assembly of functional biomolecular condensates often involves liquid-liquid phase separation (LLPS) of proteins with multiple modular domains, which can be folded or conformationally disordered to various degrees. To understand the LLPS-driving domain-domain interactions, a fundamental question is how readily the interactions in the condensed phase can be inferred from inter-domain interactions in dilute solutions. In particular, are the interactions leading to LLPS exclusively those underlying the formation of discrete inter-domain complexes in homogeneous solutions? We address this question by developing a mean-field LLPS theory of two stoichiometrically constrained solute species. The theory is applied to the neuronal proteins SynGAP and PSD-95, whose complex coacervate serves as a rudimentary model for neuronal postsynaptic densities (PSDs). The predicted phase behaviors are compared with experiments. Previously, a three-SynGAP, two-PSD-95 ratio was determined for SynGAP/PSD-95 complexes in dilute solutions. However, when this 3:2 stoichiometry is uniformly imposed in our theory encompassing both dilute and condensed phases, the tie-line pattern of the predicted SynGAP/PSD-95 phase diagram differs drastically from that obtained experimentally. In contrast, theories embodying alternate scenarios postulating auxiliary SynGAP-PSD-95 as well as SynGAP-SynGAP and PSD-95-PSD-95 interactions in addition to those responsible for stoichiometric SynGAP/PSD-95 complexes produce tie-line patterns consistent with experiment. Hence, our combined theoretical-experimental analysis indicates that weaker interactions or higher-order complexes beyond the 3:2 stoichiometry, but not yet documented, are involved in the formation of SynGAP/PSD-95 condensates, imploring future efforts to ascertain the nature of these auxiliary interactions in PSD-like LLPS.
arXiv comment38 pages, 5 figures. Accepted for publication in Biophysical Journal
References in corpus (13)
- Comparative Roles of Charge, and Hydrophobic Interactions in Sequence-Dependent Phase Separation of Intrinsically Disordered Proteins
- Sequence-specific polyampholyte phase separation in membraneless organelles
- Model for disordered proteins with strongly sequence-dependent liquid phase behavior
- Phase transitions in biological systems with many components
- Charge Pattern Matching as a "Fuzzy" Mode of Molecular Recognition for the Functional Phase Separations of Intrinsically Disordered Proteins
- Coarse-Grained Residue-Based Models of Disordered Protein Condensates: Utility and Limitations of Simple Charge Pattern Parameters
- A Lattice Model of Charge-Pattern-Dependent Polyampholyte Phase Separation
- A unified analytical theory of heteropolymers for sequence-specific phase behaviors of polyelectrolytes and polyampholytes
- Analytical Theory for Sequence-Specific Binary Fuzzy Complexes of Charged Intrinsically Disordered Proteins
- A Simple Explicit-Solvent Model of Polyampholyte Phase Behaviors and its Ramifications for Dielectric Effects in Biomolecular Condensates
- Subcompartmentalization of polyampholyte species in organelle-like condensates is promoted by charge pattern mismatch and strong excluded-volume interaction
- Finite-size scaling analysis of protein droplet formation
- Phase behavior of blocky charge lattice polymers: Crystals, liquids, sheets, filaments and clusters