Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding
| Autor: | Mingjie Zhang, Bowen Jia, Yi-Hsuan Lin, Haowei Wu, Hue Sun Chan |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
0303 health sciences
Coacervate Chemistry Biophysics Biomolecules (q-bio.BM) 03 medical and health sciences 0302 clinical medicine Quantitative Biology - Biomolecules Homogeneous Postsynaptic potential Chemical physics FOS: Biological sciences Phase (matter) 030217 neurology & neurosurgery Stoichiometry 030304 developmental biology Phase diagram |
| Zdroj: | Biophysical Journal. 121:157-171 |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/j.bpj.2021.10.008 |
| Popis: | 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. Comment: 38 pages, 5 figures. Accepted for publication in Biophysical Journal |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|