Phase separation of protein mixtures is driven by the interplay of homotypic and heterotypic interactions

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Sept. 8, 2023

Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via phase separation coupled to percolation. Intracellular often encompass numerous proteins with PLCDs. Here, we combine simulations experiments study mixtures PLCDs from two RNA-binding proteins, hnRNPA1 FUS. Using experiments, find 1:1 A1-LCD FUS-LCD undergo more readily than either on their own due complementary electrostatic interactions. Tie line analysis reveals stoichiometric ratios different components sequence-encoded interactions contribute jointly driving forces for condensate formation. Simulations also show spatial organization within is governed by relative strengths homotypic versus heterotypic We uncover rules how interaction sequence lengths modulate conformational preferences molecules at interfaces formed proteins.

Language: Английский

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Expanding the molecular language of protein liquid–liquid phase separation

Nature Chemistry, Journal Year: 2024, Volume and Issue: 16(7), P. 1113 - 1124

Published: March 29, 2024

Language: Английский

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Expanding the molecular language of protein liquid-liquid phase separation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 3, 2023

Abstract Understanding the relationship between an amino acid sequence and its phase separation has important implications for analyzing cellular function, treating disease, designing novel biomaterials. Several features have been identified as drivers protein liquid-liquid (LLPS), leading to development of a “molecular grammar” LLPS. In this work, we further probed how modulates material properties resulting condensates. Specifically, used model intrinsically disordered polypeptide composed 8-residue repeat unit performed systematic manipulations targeting previously overlooked in literature. We generated sequences with no charged residues, high net charge, glycine or devoid aromatic arginine residues. report that all but one twelve variants designed undergo LLPS, albeit different extents, despite significant differences composition. These results support hypothesis multiple interactions diverse residue pairs work tandem drive separation. Molecular simulations paint picture underlying molecular details involving various atomic mediated by not just handful types, most characterized changes inter-residue contacts variants, thereby developing more complete understanding contributions such hydrophobicity, aromaticity Further, find condensates formed behave like viscous fluids, large their viscosities. The presented study significantly advance current sequence-phase behavior sequence-material relationships help interpret, model, design assembly.

Language: Английский

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Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 25, 2024

Abstract Although our understanding of the involvement heterochromatin architectural factors in shaping nuclear organization is improving, there still ongoing debate regarding role active genes this process. In study, we utilize publicly-available Micro-C data from mouse embryonic stem cells to investigate relationship between gene transcription and 3D folding. Our analysis uncovers a nonmonotonic - globally positive correlation intragenic contact density Pol II occupancy, independent cohesin-based loop extrusion. Through development biophysical model integrating dynamics within polymer chromosome organization, demonstrate that II-mediated attractive interactions with limited valency transcribed regions yield quantitative predictions consistent chromosome-conformation-capture live-imaging experiments. work provides compelling evidence transcriptional activity shapes 4D genome through micro-compartmentalization.

Language: Английский

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Encoding Structure in Intrinsically Disordered Protein Biomaterials

Accounts of Chemical Research, Journal Year: 2024, Volume and Issue: 57(3), P. 302 - 311

Published: Jan. 9, 2024

In nature, proteins range from those with highly ordered secondary and tertiary structures to that completely lack a well-defined three-dimensional structure, termed intrinsically disordered (IDPs). IDPs are generally characterized by one or more segments have compositional bias toward small hydrophilic amino acids proline residues promote structural disorder called regions (IDRs). The combination of IDRs the interactions between two determine phase behavior, function IDPs. Nature also diversifies structure thereby their functions hybridization other moieties such as glycans lipids; for instance, post-translationally glycosylated lipidated important cell membrane components. Additionally, diversity in protein is achieved nature through cross-linking within themselves domains create various topologies. For example, an essential characteristic extracellular matrix (ECM) its network components, including collagen elastin, well polysaccharides hyaluronic acid (HA). Inspired synthetic IDP (SynIDP)-based biomaterials can be designed employing similar strategies goal introducing hence unique physiochemical properties. This Account describes materials produced over past decade following approaches: (1) incorporating into SynIDPs, (2) conjugating SynIDPs either genetically encoded post-translational modification chemical conjugation, (3) engineering topology via modification. These approaches introduce modifications primary which then translated structures. Beginning point origin, may introduced each these three individually along orthogonal axes combinations three, enabling bioinspired designs theoretically span entire possibilities. Furthermore, resultant wide length scales, nano- meso- micro- even macrostructures. this Account, emphasis placed on properties features described materials. Conjugates polymers simple mixing components outside scope Account. Related biomedical applications briefly. Finally, we note future directions design functional SynIDP-based biomaterials.

Language: Английский

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Conformational ensembles of the human intrinsically disordered proteome: Bridging chain compaction with function and sequence conservation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 8, 2023

Abstract Intrinsically disordered proteins and regions (collectively IDRs) are pervasive across proteomes in all kingdoms of life, help shape biological functions, involved numerous diseases. IDRs populate a diverse set transiently formed structures, yet defy commonly held sequence-structure-function relationships. Recent developments protein structure prediction have led to the ability predict three-dimensional structures folded at proteome scale, enabled large-scale studies structure-function In contrast, knowledge conformational properties is scarce, part because sequences poorly conserved only few been characterized experimentally. We developed an efficient model generate ensembles IDRs, thereby their from sequence only. Here, we applied this simulate human proteome. Examining 29,998 show how chain compaction correlated with cellular function localization, including different types biomolecular condensates. train use conservation structural orthologs. Our results recapitulate observations previous individual systems, enable us study relationship between sequence, conservation, ensembles, disease variants scale.

Language: Английский

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Toward Accurate Simulation of Coupling between Protein Secondary Structure and Phase Separation

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 146(1), P. 342 - 357

Published: Dec. 19, 2023

Intrinsically disordered proteins (IDPs) frequently mediate phase separation that underlies the formation of a biomolecular condensate. Together with theory and experiment, efficient coarse-grained (CG) simulations have been instrumental in understanding sequence-specific IDPs. However, widely used Cα-only models are limited capturing peptide nature IDPs, particularly backbone-mediated interactions effects secondary structures, separation. Here, we describe hybrid resolution (HyRes) protein model toward more accurate description backbone transient structures With an atomistic side chains, HyRes can semiquantitatively capture residue helical propensity overall chain dimension monomeric Using GY-23 as system, show is enough for direct simulation spontaneous and, at same time, appears to resolve single His Lys mutations. also successfully predict increased β-structure condensate, consistent available experimental CD data. We further utilize study TPD-43, where several disease-related mutants conserved region (CR) shown affect residual helicities modulate measured by saturation concentration. The recapitulate effect these on helicity TDP-43 CR. Analyses reveal balance between chain-mediated interactions, but not itself, actually determines propensity. These results support represents effective molecular IDP will help elucidate coupling

Language: Английский

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Phase separation of multicomponent peptide mixtures into dehydrated clusters with hydrophilic cores

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(3), P. 349 - 360

Published: Jan. 1, 2024

Language: Английский

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Dynamics and interactions of intrinsically disordered proteins

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 84, P. 102734 - 102734

Published: Nov. 30, 2023

Language: Английский

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Phase Separation in Mixtures of Prion-Like Low Complexity Domains is Driven by the Interplay of Homotypic and Heterotypic Interactions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 16, 2023

Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via coupled associative segregative phase transitions. We previously deciphered how evolutionarily conserved sequence features drive separation PLCDs through homotypic interactions. However, typically encompass a diverse mixture proteins with PLCDs. Here, we combine simulations experiments to study mixtures from two RNA binding namely, hnRNPA1 FUS. find 1:1 A1-LCD FUS-LCD undergo more readily than either on their own. The enhanced driving forces for arise partly complementary electrostatic interactions between proteins. This complex coacervation-like mechanism adds among aromatic residues. Further, tie line analysis shows stoichiometric ratios different components sequence-encoded jointly contribute condensate formation. These results highlight expression levels might be tuned regulate vivo . Simulations also show organization within deviates expectations based random models. Instead, spatial will reflect relative strengths versus heterotypic uncover rules interaction lengths modulate conformational preferences molecules at interfaces formed by Overall, our findings emphasize network-like multicomponent condensates, distinctive, composition-specific interfaces.Biomolecular protein nucleic acid organize biochemical reactions cells. Much what know about comes studies transitions individual condensates. report archetypal feature Our investigations, aided blend computations experiments, governed interplay point can cells internal structures, compositions, thus affording ways control functions

Language: Английский

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