![]() ![]() (18) Taking a reductionist approach, we reason that the “stickers-and-spacers” (18) interaction mode with prominent multivalency (12,19,20) can help extract the molecular determinants of LLPS of IDPs. (18) Modules driving molecular attractions are considered as “stickers”, while modules providing a flexible linkage between “stickers” with no significant attractions are considered as “spacers”. #Protein scaffold minimal freeThe intricate molecular interactions implicated in IDPs can be depicted using a simplified “stickers-and-spacers” (17) framework derived from Flory–Huggins theory, wherein the mean-field free energy was enhanced from “sticker” interactions. Notwithstanding, a chemically synthetic construct to recapitulate the essential features of IDP is yet to be reported. Reported in natural living cells (7−10) and reconstituted systems in vitro, (11−15) large low-complexity domains (8,12,16) (usually over 100 residues) or engineered proteins harboring low-complexity domains (11−13) are the building blocks for LLPS. (5) Most MLOs contain IDPs harboring low-complexity domains, (6) which are responsible for driving LLPS via weak and multivalent interactions. (2,3) In contrast to the stable and static amyloid-like structures, (4) MLO structures are labile, dynamic, and reversible. MLOs have aroused intense interests from multidisciplinary scientists owing to the ubiquitous biological implications in cellular physiology and disease. Besides lipid bilayer membrane-delimited compartmentalization, (1) membraneless organelles (MLOs) formed by liquid–liquid phase separation (LLPS) provide another universal intracellular organization. This simple yet versatile model system can help elucidate the molecular interactions implicated in MLOs and pave ways to a new type of biomimetic materials.Ĭellular metabolism requires precise spatiotemporal regulation of numerous biomolecules. Moreover, the droplets formed are capable of recruiting proteins and RNAs and providing a favorable environment for a biochemical reaction with highly enriched components, thereby mimicking the function of natural MLOs. Hybrids undergo LLPS into micron-sized liquid droplets resembling LLPS in vitro and in living cells. Here, we report the first design of synthetic hybrids consisting of short oligopeptides of fewer than 10 residues as “stickers” and dextran as a “spacer” to recapitulate the characteristics of IDPs, as exemplified by the multivalent FUS protein. Genetic engineering is generally applied to reconstruct IDPs harboring over 100 amino acid residues. Liquid–liquid phase separation (LLPS) is an emerging and universal mechanism for intracellular organization, particularly, by forming membraneless organelles (MLOs) hosting intrinsically disordered proteins (IDPs) as scaffolds. ![]()
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