Stochasticity of Biological Soft Matter: Emerging Concepts in Intrinsically Disordered Proteins and Biological Phase Separation

Turoverov, Konstantin К.; Kuznetsova, Irina М.; Fonin, Alexander V.; Darling, April L.; Zaslavsky, Boris Y.; Uversky, Vladimir N.

doi:10.1016/j.tibs.2019.03.005

Cited by 103 publications

(77 citation statements)

References 107 publications

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“…Nonetheless, micrometer-sized clusters of proteins can occur at membranes and have been associated with the synaptic activity, 71,72 addressing a possible role for PrP C phase separation as signaling hubs at the plasma membrane. 77 These PrP-induced ribonucleoprotein granules harbor the characteristics of intracellular membrane-less organelles, 61 supporting the idea that PrP may undergo LLPS in vivo and its dysregulation might evolve to pathogenic states. 73,74 For GPI-anchored proteins, it is well-established that they cycle along the secretory pathway, being translocated to the ER after synthesis, and transported to the Golgi apparatus before being directed to the plasma membrane.…”

Section: Discussionmentioning

confidence: 81%

“…Furthermore, formation of ribonucleoprotein particles induced by a cytosolic form of PrP was previously described. 77 These PrP-induced ribonucleoprotein granules harbor the characteristics of intracellular membrane-less organelles, 61 supporting the idea that PrP may undergo LLPS in vivo and its dysregulation might evolve to pathogenic states. Phase transition driven by the DNA aptamers was dependent on the complex stoichiometry, a characteristic of proteins that undergo LLPS, such as FUS and TDP-43.…”

Section: Discussionmentioning

confidence: 81%

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Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

et al. 2019

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Structural conversion of cellular prion protein (PrP C ) into scrapie PrP (PrP Sc ) and subsequent aggregation are key events associated with the onset of transmissible spongiform encephalopathies (TSEs). Experimental evidence supports the role of nucleic acids (NAs) in assisting this conversion. Here, we asked whether PrP undergoes liquid-liquid phase separation (LLPS) and if this process is modulated by NAs. To this end, two 25-mer DNA aptamers, A1 and A2, were selected against the globular domain of recombinant murine PrP (rPrP 90-231 ) using SELEX methodology. Multiparametric structural analysis of these aptamers revealed that A1 adopts a hairpin conformation. Aptamer binding caused partial unfolding of rPrP 90-231 and modulated its ability to undergo LLPS and fibrillate. In fact, although free rPrP phase separated into large droplets, aptamer binding increased the number of droplets but noticeably reduced their size. Strikingly, a modified A1 aptamer that does not adopt a hairpin structure induced formation of amyloid fibrils on the surface of the droplets. We show here that PrP undergoes LLPS, and that the PrP interaction with NAs modulates phase separation and promotes PrP fibrillation in a NA structure and concentration-dependent manner. These results shed new light on the roles of NAs in PrP misfolding and TSEs. |

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 81%

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

et al. 2019

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“…When ELPs are crosslinked or hybridized with graphene, the resulting hydrogels can be made into shape‐memory hydrogels, thermosensors, light‐controlled actuators, and other flexible electronics . Moreover, the phase transition behaviors of IDPs, together with their catalytic function, are often activated upon combining with IDP‐binding RNA during the formation of liquid organelles, which inspires novel design of electric valves in semiconductors, biosensors, robots, and other smart devices . Furthermore, understanding of the reversibility of the liquid–liquid phase transition of membraneless organelles offers new promises to the diagnosis and therapeutic control of organelle diseases.…”

Section: Conclusion and Outlooksmentioning

confidence: 99%

Cell‐Inspired All‐Aqueous Microfluidics: From Intracellular Liquid–Liquid Phase Separation toward Advanced Biomaterials

et al. 2020

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Living cells have evolved over billions of years to develop structural and functional complexity with numerous intracellular compartments that are formed due to liquid–liquid phase separation (LLPS). Discovery of the amazing and vital roles of cells in life has sparked tremendous efforts to investigate and replicate the intracellular LLPS. Among them, all‐aqueous emulsions are a minimalistic liquid model that recapitulates the structural and functional features of membraneless organelles and protocells. Here, an emerging all‐aqueous microfluidic technology derived from micrometer‐scaled manipulation of LLPS is presented; the technology enables the state‐of‐art design of advanced biomaterials with exquisite structural proficiency and diversified biological functions. Moreover, a variety of emerging biomedical applications, including encapsulation and delivery of bioactive gradients, fabrication of artificial membraneless organelles, as well as printing and assembly of predesigned cell patterns and living tissues, are inspired by their cellular counterparts. Finally, the challenges and perspectives for further advancing the cell‐inspired all‐aqueous microfluidics toward a more powerful and versatile platform are discussed, particularly regarding new opportunities in multidisciplinary fundamental research and biomedical applications.

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“…Consequently, dysregulation of IDPs/IDRs are associated with a variety of human diseases . Most recently, many IDPs/IDRs are found to be able to undergo liquid–liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo . So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence–structure–function relationship of proteins .…”

Section: Introductionmentioning

confidence: 99%

“…[32][33][34][35][36][37][38][39][40][41][42][43][44] Most recently, many IDPs/IDRs are found to be able to undergo liquid-liquid phase separation (LLPS), which is related to the assembling of membraneless organelles in vivo. [45][46][47][48][49][50][51][52][53] So far, studies on IDPs/IDRs have greatly extended our understanding on the sequence-structurefunction relationship of proteins. 29,[54][55][56] Recently, the protein structure-function continuum concept was proposed by Uversky to illustrate the numerous biological functions of p53 through multiple proteoforms by various mechanisms and may be extended to many multi-function IDPs.…”

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confidence: 99%

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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The sequence–structure–function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well‐defined three‐dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

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Stochasticity of Biological Soft Matter: Emerging Concepts in Intrinsically Disordered Proteins and Biological Phase Separation

Cited by 103 publications

References 107 publications

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

Liquid‐liquid phase separation and fibrillation of the prion protein modulated by a high‐affinity DNA aptamer

Cell‐Inspired All‐Aqueous Microfluidics: From Intracellular Liquid–Liquid Phase Separation toward Advanced Biomaterials

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

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