Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding

Lin，Yi Hsuan1,2; Wu，Haowei3; Jia，Bowen3; Zhang，Mingjie3,4; Chan，Hue Sun1

2021

10.1016/j.bpj.2021.10.008

BIOPHYSICAL JOURNAL   影响因子和分区

0006-3495

1542-0086

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 interdomain interactions in dilute solutions. In particular, are the interactions leading to LLPS exclusively those underlying the formation of discrete interdomain 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 and underscoring a likely general synergy between stoichiometric, structurally specific binding and stochastic, multivalent “fuzzy” interactions in the assembly of functional biomolecular condensates.

SCI

英语

通讯

Canadian Institutes of Health Research[NJT-155930] ; Natural Sciences and Engineering Research Council of Canada[RGPIN-2018-04351] ; National Key R&D Program of China[2019YFA0508402] ; Research Grants Council of Hong Kong[AoE-M09-12]

Biophysics

Biophysics

WOS:000740815400016

CELL PRESS

BIOLOGY & BIOCHEMISTRY

2-s2.0-85118253392

Scopus

1.Department of Biochemistry,University of Toronto,Ontario,Toronto,Canada
2.Molecular Medicine,The Hospital for Sick Children,Ontario,Toronto,Canada
3.Division of Life Science,State Key Laboratory of Molecular Neuroscience,Hong Kong University of Science and Technology,Clear Water Bay,Hong Kong,Hong Kong
4.School of Life Sciences,Southern University of Science and Technology,Shenzhen,China

Lin，Yi Hsuan,Wu，Haowei,Jia，Bowen,et al. Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding[J]. BIOPHYSICAL JOURNAL,2021,121(1).

Lin，Yi Hsuan,Wu，Haowei,Jia，Bowen,Zhang，Mingjie,&Chan，Hue Sun.(2021).Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding.BIOPHYSICAL JOURNAL,121(1).

Lin，Yi Hsuan,et al."Assembly of model postsynaptic densities involves interactions auxiliary to stoichiometric binding".BIOPHYSICAL JOURNAL 121.1(2021).