Complex microparticle architectures from stimuli-responsive intrinsically disordered proteins

Roberts, Stefan; Miao, Vincent N.; Costa, Sérgio Ely Valadão Gigante de Andrade; Simon, Joseph R.; Kelly, Garrett; Shah, Tejank; Zauscher, Stefan; Chilkoti, Ashutosh

doi:10.1038/s41467-020-15128-9

Cited by 56 publications

(61 citation statements)

References 55 publications

(74 reference statements)

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“…In that respect, computer simulations emerges as a great tool to enlighten this blind spot 6,[72][73][74] . The most recent advances in computational science have allowed to carry out impressive calculations mimicking in vivo conditions 75 .…”

Section: Introductionmentioning

confidence: 99%

RNA modulation of transport properties and stability in phase separated condensates

Tejedor

Garaizar

Ramı́rez

et al. 2021

Preprint

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One of the key mechanisms employed by cells to control their spatiotemporal organization is the formation and dissolution of phase-separated condensates. Such balance between condensate assembly and disassembly can be critically regulated by the presence of RNA. In this work, we use a novel chemically accurate coarse-grained model for proteins and RNA to unravel the impact of poly-uridine RNA in modulating the protein mobility and stability within different biomolecular condensates. We explore the behavior of FUS, hnRNPA1 and TDP-43 proteins along their corresponding prion-like domains from absence to moderately high RNA concentration. By characterising the phase diagram, key molecular interactions, surface tension and viscoelastic properties, we report a dual RNA-induced behavior: On the one hand, poly-uridine enhances phase separation at low concentration, whilst at high concentration, it inhibits the ability of proteins to self-assemble. On the other hand, as a consequence of such stability modulation, the transport properties of proteins within the condensates are significantly enhanced at moderately high RNA concentration, as long as the length of poly-uridine strands is comparable or moderately shorter than those of the proteins. On the whole, our work elucidates the different routes by which RNA can regulate phase separation and condensate dynamics, as well as the subsequent aberrant rigidification implicated in the emergence of various neuropathologies and age-related diseases.

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Section: Introductionmentioning

confidence: 99%

RNA modulation of transport properties and stability in phase separated condensates

Tejedor

Garaizar

Ramı́rez

et al. 2021

Preprint

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“…Developing LLPS models with transferable interaction potentials applicable to a wide range of amino acid sequences is essential for advancing fundamental physical understanding of natural biomolecular condensates and engineering of bioinspired materials (66). In this endeavor, the rapidly expanding repertoire of experimental data offers critical assessment of theoretical and computational approaches.…”

mentioning

confidence: 99%

Comparative roles of charge, π , and hydrophobic interactions in sequence-dependent phase separation of intrinsically disordered proteins

Das

Lin

Vernon

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

207

302

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Endeavoring toward a transferable, predictive coarse-grained explicit-chain model for biomolecular condensates underlain by liquid–liquid phase separation (LLPS) of proteins, we conducted multiple-chain simulations of the N-terminal intrinsically disordered region (IDR) of DEAD-box helicase Ddx4, as a test case, to assess roles of electrostatic, hydrophobic, cation–π, and aromatic interactions in amino acid sequence-dependent LLPS. We evaluated three different residue–residue interaction schemes with a shared electrostatic potential. Neither a common hydrophobicity scheme nor one augmented with arginine/lysine-aromatic cation–π interactions consistently accounted for available experimental LLPS data on the wild-type, a charge-scrambled, a phenylalanine-to-alanine (FtoA), and an arginine-to-lysine (RtoK) mutant of Ddx4 IDR. In contrast, interactions based on contact statistics among folded globular protein structures reproduce the overall experimental trend, including that the RtoK mutant has a much diminished LLPS propensity. Consistency between simulation and experiment was also found for RtoK mutants of P-granule protein LAF-1, underscoring that, to a degree, important LLPS-driving π-related interactions are embodied in classical statistical potentials. Further elucidation is necessary, however, especially of phenylalanine’s role in condensate assembly because experiments on FtoA and tyrosine-to-phenylalanine mutants suggest that LLPS-driving phenylalanine interactions are significantly weaker than posited by common statistical potentials. Protein–protein electrostatic interactions are modulated by relative permittivity, which in general depends on aqueous protein concentration. Analytical theory suggests that this dependence entails enhanced interprotein interactions in the condensed phase but more favorable protein–solvent interactions in the dilute phase. The opposing trends lead to only a modest overall impact on LLPS.

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“…Recent studies have evidenced that ordered domains highly modulate the hierarchical assembly of the IDPPs into complex architectures. 20,55 In this regard, the synergistic combination of AMPs and IDPPs opens up a wide range of possibilities for the fabrication of hierarchical nanomaterials with advanced functionalities for biotechnology and biomedical engineering.…”

Section: Thermoresponsive Nanostructuresmentioning

confidence: 99%

Dual Self-Assembled Nanostructures from Intrinsically Disordered Protein Polymers with LCST Behavior and Antimicrobial Peptides

Acosta

Aparicio

et al. 2020

Biomacromolecules

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Antimicrobial peptides (AMPs) have attracted great interest as they constitute one of the most promising alternatives against drug-resistant infections. Their amphipathic nature provides them antimicrobial and immunomodulatory properties but also the ability to self-assemble into 2 supramolecular nanostructures. Here, we propose their use as self-assembling domains to drive hierarchical organization of intrinsically disordered protein polymers (IDPPs). Using a modular approach, hybrid protein-engineered polymers were recombinantly produced, thus combining designer AMPs and a thermoresponsive IDPP, an elastin-like recombinamer (ELR). We exploited the ability of these AMPs and ELRs to self-assemble to develop supramolecular nanomaterials by way of a dual-assembly process. First, the AMPs trigger the formation of nanofibers, then the thermoresponsiveness of the ELRs enables assembly into fibrillar aggregates. The interplay between the assembly of AMPs and ELRs provides an innovative molecular tool in the development of self-assembling nanosystems with potential use for biotechnological and biomedical applications.

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Complex microparticle architectures from stimuli-responsive intrinsically disordered proteins

Cited by 56 publications

References 55 publications

RNA modulation of transport properties and stability in phase separated condensates

RNA modulation of transport properties and stability in phase separated condensates

Comparative roles of charge, π , and hydrophobic interactions in sequence-dependent phase separation of intrinsically disordered proteins

Dual Self-Assembled Nanostructures from Intrinsically Disordered Protein Polymers with LCST Behavior and Antimicrobial Peptides

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