Divergent evolution of low-complexity regions in the vertebrate CPEB protein family

Frontiers in Bioinformatics, Journal Year: 2025, Volume and Issue: 5

Published: March 20, 2025

The cytoplasmic polyadenylation element-binding proteins (CPEBs) are a family of translational regulators involved in multiple biological processes, including memory-related synaptic plasticity. In vertebrates, four paralogous genes (CPEB1-4) encode with phylogenetically conserved C-terminal RNA-binding domains and variable N-terminal regions (NTRs). CPEB NTRs characterized by low-complexity (LCRs), homopolymeric amino acid repeats (AARs), have been identified as mediators liquid-liquid phase separation (LLPS) prion-like aggregation. After their appearance following gene duplication, the functionally diverged terms activation mechanisms modes mRNA binding. paralog-specific may contributed substantially to such functional diversification but evolutionary history remains largely unexplored. Here, we traced evolution vertebrate CPEBs LCRs/AARs focusing on primary sequence composition, complexity, repetitiveness, possible impact LLPS propensity prion-likeness. We initially defined these composition- function-related quantitative parameters for human paralogs then systematically analyzed variation across more than 500 species belonging nine major clades different stem age, from Chondrichthyes Euarchontoglires, along lineage. found that display highly divergent, trends parameters, primarily driven related clade ages. These findings shed new light molecular LCRs protein family, both qualitative terms, highlighting emergence CPEB2 proline-rich younger clades, Primates.

Language: Английский

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Sequence-Encoded Spatiotemporal Dependence of Viscoelasticity of Protein Condensates Using Computational Microrheology

JACS Au, Journal Year: 2024, Volume and Issue: 4(11), P. 4394 - 4405

Published: Nov. 11, 2024

Many biomolecular condensates act as viscoelastic complex fluids with distinct cellular functions. Deciphering the behavior of can provide insights into their spatiotemporal organization and physiological roles within cells. Although there is significant interest in defining role condensate dynamics rheology functions, quantification time-dependent properties limited mostly done through experimental rheological methods. Here, we demonstrate that a computational passive probe microrheology technique, coupled continuum mechanics, accurately characterize linear viscoelasticity formed by intrinsically disordered proteins (IDPs). Using transferable coarse-grained protein model, first physical basis for choosing optimal values define attributes particle, namely, its size interaction strength residues an IDP chain. We show technique captures sequence-dependent heteropolymeric IDPs differ either sequence charge patterning or hydrophobicity. also illustrate technique's potential quantifying spatial dependence heterogeneous condensates. The has important implications investigating architectures, resulting sequence–rheology–function relationship

Language: Английский

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Sequence-encoded Spatiotemporal Dependence of Viscoelasticity of Protein Condensates Using Computational Microrheology

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 16, 2024

Many biomolecular condensates act as viscoelastic complex fluids with distinct cellular functions. Deciphering the behavior of can provide insights into their spatiotemporal organization and physiological roles within cells. Though there is significant interest in defining role condensate dynamics rheology functions, quantification time-dependent properties limited mostly done through experimental rheological methods. Here, we demonstrate that a computational passive probe microrheology technique, coupled continuum mechanics, accurately characterize linear viscoelasticity formed by intrinsically disordered proteins (IDPs). Using transferable coarse-grained protein model, first physical basis for choosing optimal values define attributes particle, namely its size interaction strength residues an IDP chain. We show technique captures sequence-dependent heteropolymeric IDPs differ either sequence charge patterning or hydrophobicity. also illustrate technique's potential quantifying spatial dependence heterogeneous condensates. The has important implications investigating time dependent architectures, resulting sequence-rheology-function relationship

Language: Английский

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Disordered proteins: microphases or associative polymers?

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 11, 2024

We develop a surrogate model for low complexity disordered proteins, which allows us to generate sequences with quantifiable disorder. investigate properties of these sequences, and show that the sequence dependence radius gyration only arises in vicinity polymer collapse transition. Microphase propensity is shown be reliable predictor, outperforming state art methods, crossover region. predictions associative theory as limiting case, discuss its applicability.

Language: Английский

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Amino Acid Transfer Free Energies Reveal Thermodynamic Driving Forces in Biomolecular Condensate Formation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 5, 2024

The self-assembly of intrinsically disordered proteins into biomolecular condensates shows a dependence on the primary sequence protein, leading to sequence-dependent phase separation. Methods investigate this separation rely effective residue-level interaction potentials that quantify propensity for residues remain in dilute versus dense phase. most direct measure these are distribution coefficients different amino acids between two phases, but due lack availability coefficients, proxies, notably hydropathy, have been used. However, recent work has demonstrated limitations assumption hydropathy-driven In work, we address fundamental gap by calculating transfer free energies associated with transferring each acid side chain analog from model condensate. We uncover an interplay favorable protein-mediated and unfavorable water-mediated contributions overall transfer. further asymmetry positive negative charges driving forces condensate formation. results presented provide explanation several non-trivial trends observed literature will aid interpretation experiments aimed at elucidating underlying formation condensates.

Language: Английский

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