Phase Transitions in the Assembly of Multi-Valent Signaling Proteins

By Pilong Li, Sudeep Banjade, Hui-Chun Cheng, Soyeon Kim, Baoyu Chen, Liang Guo, M. Llaguno, Javoris V. Hollingsworth, David S. King, Salman F. Banani and 4 more. Nature, 2012

2,275 citations recorded by the source corpus.

Cells are organized on length scales ranging from ångström to micrometres. However, the mechanisms by which ångström-scale molecular properties are translated to micrometre-scale macroscopic properties are not well understood. Here we show that interactions between diverse synthetic, multivalent macromolecules (including multi-domain proteins and RNA) produce sharp liquid–liquid-demixing phase separations, generating micrometre-sized liquid droplets in aqueous solution. This macroscopic transition corresponds to a molecular transition between small complexes and large, dynamic supramolecular polymers. The concentrations needed for phase transition are directly related to the valency of the interacting species. In the case of the actin-regulatory protein called neural Wiskott–Aldrich syndrome protein (N-WASP) interacting with its established biological partners NCK and phosphorylated nephrin, the phase transition corresponds to a sharp increase in activity towards an actin nucleation factor, the Arp2/3 complex. The transition is governed by the degree of phosphorylation of nephrin, explaining how this property of the system can be controlled to regulatory effect by kinases. The widespread occurrence of multivalent systems suggests that phase transitions may be used to spatially organize and biochemically regulate information throughout biology.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2645307e0d28a3b78c0bf2897ea6cc54b01c962e

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Citations in the corpus

G3BP1 is a tunable switch that triggers phase separation to assemble stress granules (2020, neutral): “This inverse correlation between fluidity of a biomolecular condensate and interaction valency of its constituents is consistent with observations in vitro (Li et al., 2012) and may reflect a general principle controlling material properties of biomolecular condensates.”
Liquid-liquid phase separation in biology. (2014, background): “Indeed, in a recent groundbreaking study, Li et al. (2012) showed in vitro that multivalent weak interactions between signaling proteins can drive the formation of liquid drops.”
Palmitic Acid: Physiological Role, Metabolism and Nutritional Implications (2017, background): “Unless palmitoyl-CoA is enriched in specific membrane microdomains (Li et al., 2012), its small concentration doesn’t permit spontaneous palmitoylation of proteins and S-palmitoylation is thus mediated by palmitoyltransferases (Fukata and Fukata, 2010).”
Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization (2015, positive): “LLPS has been proposed as the molecular mechanism underlying formation of membrane-less cellular bodies that exhibit liquid properties, such as P granules and nucleoli (Brangwynne et al., 2009; Elbaum-Garfinkle et al., 2015; Fromm et al., 2014; Li et al., 2012; Nott et al., 2015).”
Compositional Control of Phase-Separated Cellular Bodies (2016, positive): “First, scaffolds self-associate by multivalent heterotypic interactions and undergo assembly-driven phase separation (Li et al., 2012), forming a condensed phase (Figure 7A)—i.e., the cellular body.”
Formation and Maturation of Phase Separated Liquid Droplets by RNA Binding Proteins (2015, background): “In a related process, interactions between multivalent proteins and their multivalent ligands (both protein and RNA) can produce LLPS, concomitant with assembly into large oligomers and polymers (Li et al., 2012; Banjade and Rosen, 2014).”
Phase separation in biology; functional organization of a higher order (2016, background): “PRM Proline-rich short linear motif SH3 domain binding [46] Mitrea and Kriwacki Cell Communication and Signaling (2016) 14:1 Page 7 of 20”
Programming molecular self-assembly of intrinsically disordered proteins containing sequences of low complexity (2017, positive): “Although ELPs and phase-separating intracellular IDPs differ substantially in their sequence composition, their sequences share three key features: (1) highly repetitive, (2) of low complexity and (3) enriched in a limited set of similar disorder-promoting amino acids, which leads to a high propensi”