HDX–MS finds that partial unfolding with sequential domain activation controls condensation of a cellular stress marker

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(13)

Published: March 21, 2024

Eukaryotic cells form condensates to sense and adapt their environment [S. F. Banani, H. O. Lee, A. Hyman, M. K. Rosen, Nat. Rev. Mol. Cell Biol. 18 , 285–298 (2017), Yoo, C. Triandafillou, D. Drummond, J. Chem. 294 7151–7159 (2019)]. Poly(A)-binding protein (Pab1), a canonical stress granule marker, condenses upon heat shock or starvation, promoting adaptation [J. Riback et al. 168 1028–1040.e19 (2017)]. The molecular basis of condensation has remained elusive due dearth techniques probe structure directly in condensates. We apply hydrogen–deuterium exchange/mass spectrometry investigate the mechanism Pab1’s condensation. four RNA recognition motifs (RRMs) undergo different levels partial unfolding condensation, changes are similar for thermal pH stresses. Although structural heterogeneity is observed, ability MS describe populations allows us identify which regions contribute condensate’s interaction network. Our data yield picture stress-triggered we term sequential activation ( Fig. 1 A ), wherein each RRM becomes activated at temperature where it partially unfolds associates with other likewise RRMs condensate. Subsequent association dictated more by underlying free energy surface than specific interactions, an effect refer as thermodynamic specificity. study represents advance elucidating interactions that drive Furthermore, our findings demonstrate how can use specificity perform acute response multiple stresses, potentially general stress-responsive proteins.

Language: Английский

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Crosstalk between protein post-translational modifications and phase separation

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 12, 2024

Abstract The phenomenon of phase separation is quite common in cells, and it involved multiple processes life activities. However, the current research on correlation between protein modifications interference with tendency has some limitations. Here we focus several post-translational proteins, including phosphorylation modification at sites, methylation modification, acetylation ubiquitination SUMOylation etc., which regulate formation stability structure through multivalent interactions. This regulatory role closely related to development neurodegenerative diseases, tumors, viral infections, other also plays essential functions environmental stress, DNA damage repair, transcriptional regulation, signal transduction, cell homeostasis living organisms, provides an idea explore interaction novel separation.

Language: Английский

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Functional Biomaterials Derived from Protein Liquid–Liquid Phase Separation and Liquid‐to‐Solid Transition

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 9, 2025

Protein phase transitions play a vital role in both cellular functions and pathogenesis. Dispersed proteins can undergo liquid-liquid separation to form condensates, process that is reversible highly regulated within cells. The formation physicochemical properties of these such as composition, viscosity, multiphase miscibility, are precisely modulated fulfill specific biological functions. However, protein condensates further liquid-to-solid state, forming β-sheet-rich aggregates may disrupt function lead diseases. While this phenomenon crucial for processes has significant implications neurodegenerative diseases, the behavior naturally derived or engineered polypeptides also presents opportunities developing high-performance, multifunctional materials at various scales. Additionally, unique molecular recruitment capabilities inspire innovative advancements biomaterial design applications drug discovery, delivery, biosynthesis. This work highlights recent progress understanding mechanisms underlying behavior, particularly how it responds internal changes external physical stimuli. Furthermore, fabrication from diverse sources through controlled demonstrated.

Language: Английский

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Ion binding with charge inversion combined with screening modulates DEAD box helicase phase transitions

Cell Reports, Journal Year: 2023, Volume and Issue: 42(11), P. 113375 - 113375

Published: Nov. 1, 2023

Membraneless organelles, or biomolecular condensates, enable cells to compartmentalize material and processes into unique biochemical environments. While specific, attractive molecular interactions are known stabilize repulsive interactions, the balance between these opposing forces, largely unexplored. Here, we demonstrate that electrostatic regulate condensate stability, internal mobility, interfaces, selective partitioning of molecules both in vitro cells. We find signaling ions, such as calcium, alter repulsions model Ddx3 Ddx4 proteins by directly binding negatively charged amino acid sidechains effectively inverting their charge, a manner fundamentally dissimilar screening. Using polymerization combined with generalized stickers spacers, accurately quantify predict stability over wide range pH, salt concentrations, sequences. Our provides general quantitative treatment for understanding how charge ions reversibly control stability.

Language: Английский

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A Comprehensive Review on Electrochemical Nano Biosensors for Precise Detection of Blood-Based Oncomarkers in Breast Cancer

Biosensors, Journal Year: 2023, Volume and Issue: 13(4), P. 481 - 481

Published: April 16, 2023

Breast cancer (BC), one of the most common and life-threatening cancers, has highest incidence rate among women. Early diagnosis BC oncomarkers is considered effective strategy for detecting treating BC. Finding type stage in women as soon possible greatest ways to stop its negative effects on medical treatment. The development biosensors early, sensitive, selective detection recently attracted much attention. An electrochemical nano biosensor (EN) a very suitable option powerful tool diagnosis. This comprehensive review provides information about prevalence pathobiology BC, recent advances clinically available oncomarkers, point-of-care (POC) various using nanomaterial-based signal amplification techniques.

Language: Английский

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An evolutionarily conserved mechanism controls reversible amyloids of pyruvate kinase via pH-sensing regions

Developmental Cell, Journal Year: 2024, Volume and Issue: 59(14), P. 1876 - 1891.e7

Published: May 23, 2024

Language: Английский

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Phase separation-mediated biomolecular condensates and their relationship to tumor

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Feb. 21, 2024

Abstract Phase separation is a cellular phenomenon where macromolecules aggregate or segregate, giving rise to biomolecular condensates resembling "droplets" and forming distinct, membrane-free compartments. This process pervasive in biological cells, contributing various essential functions. However, when phase goes awry, leading abnormal molecular aggregation, it can become driving factor the development of diseases, including tumor. Recent investigations have unveiled intricate connection between dysregulated tumor pathogenesis, highlighting its potential as novel therapeutic target. article provides an overview recent research, with particular emphasis on role tumor, implications, outlines avenues for further exploration this intriguing field.

Language: Английский

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Metabolism: Fine and Coarse Controls

Published: Jan. 1, 2025

Language: Английский

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Gelsolin-mediated actin filament severing, mechanics, and conformational changes at neutral and acidic pH

Frontiers in Soft Matter, Journal Year: 2025, Volume and Issue: 5

Published: March 24, 2025

Gelsolin is a calcium (Ca 2+ ) dependent, pH sensitive actin-binding protein that regulates actin filament dynamics to remodel the cytoskeleton. It known gelsolin binding induces conformational changes of filaments, leading severing. However, influence physiological conditions, such as variations, on gelsolin-mediated severing activities, mechanics and conformations remains unclear despite their role in actin-actin interactions. Using Total Internal Reflection Fluorescence (TIRF) microscopy imaging pyrene fluorescence assays, we demonstrate efficiencies by are enhanced acidic conditions. In addition, analysis thermal fluctuations using TIRF reveals stiffens filaments. Furthermore, show filaments measuring half-pitch high resolution Atomic Force Microscopy imaging. Together, our results suggest modulation plays key bending mechanics, changes, which have implications many cellular processes including cell motility morphogenesis.

Language: Английский

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Liquid-liquid phase separation in cell physiology and cancer biology: recent advances and therapeutic implications

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 31, 2025

Liquid-liquid phase separation (LLPS) is a pivotal biophysical phenomenon that plays critical role in cellular organization and has garnered significant attention the fields of molecular mechanism pathophysiology cancer. This dynamic process involves spontaneous segregation biomolecules, primarily proteins nucleic acids, into condensed, liquid-like droplets under specific conditions. LLPS drives formation biomolecular condensates, which are crucial for various functions. Increasing evidences link alterations to onset progression diseases, particularly review explores diverse roles cancer, highlighting its underlying mechanisms far-reaching implications. We examine how dysregulated contributes cancer development by influencing key processes such as genomic instability, metabolism, immune evasion. Furthermore, we discuss emerging therapeutic strategies aimed at modulating LLPS, underscoring their potential revolutionize treatment.

Language: Английский

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