NMR Dynamic View of the Stabilization of the WW4 Domain by Neutral NaCl and Kosmotropic Na2SO4 and NaH2PO4 DOI Open Access

Liangzhong Lim,

Jianxing Song

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 9091 - 9091

Published: Aug. 22, 2024

The Hofmeister series categorizes ions based on their effects protein stability, yet the microscopic mechanism remains a mystery. In this series, NaCl is neutral, Na2SO4 and Na2HPO4 are kosmotropic, while GdmCl NaSCN chaotropic. This study employs CD NMR to investigate of NaCl, Na2SO4, conformation, binding, backbone dynamics (ps-ns µs-ms time scales) WW4 domain with high stability accessible side chains at concentrations ≤ 200 mM. results indicated that none three salts altered conformation or showed significant binding four aliphatic hydrophobic chains. had no effect its thermal enhanced by ~5 °C. Interestingly, only weakly interacted Arg27 amide proton, whereas bound Phe31 protons Kd 32.7 41.6 mM, respectively. Na2HPO4, however, in non-saturable manner Trp9, His24, Asn36 protons. While negligible ps-ns dynamics, displayed significantly increased dynamics. These findings, combined our recent NaSCN, suggest for series. Additionally, data revealed lack simple correlation between thermodynamic most likely due enthalpy-entropy compensation. Our rationalizes selection chloride phosphate as primary anions extracellular intracellular spaces, well polyphosphate primitive chaperone certain single-cell organisms.

Language: Английский

Protein misfolding and amyloid nucleation through liquid–liquid phase separation DOI
S. Mukherjee, Manisha Poudyal, K. Dave

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(10), P. 4976 - 5013

Published: Jan. 1, 2024

Protein misfolding and amyloid aggregation, linked to neurodegenerative diseases, can result from liquid–liquid phase separation (LLPS) a subsequent liquid-to-solid transition. This represents LLPS as generic mechanism in nucleation.

Language: Английский

Citations

25
Fluorescent Fingerprint Identification of Protein Structural Changes and Disease-Specific Amyloid Beta Aggregates Based on a Single-Nanozyme Sensor Array DOI
Xiaohai Yang, Min Zhang, Na Lü

et al.

Analytical Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

The misfolding of amyloid β (Aβ) peptides into an aggregation state is a central hallmark the onset Alzheimer's disease (AD). However, conventional methods are mainly focused on detecting specific Aβ peptide, which makes it difficult to recognize multiple analytes with different topological features and unfolded states at same time. Here, we propose simple universal sensing strategy construct fluorescence sensor array by using single-nanozyme probe combined three fluorescent substrates as recognition units protein structural changes identify between assemblies. In this system, fingerprint-like patterns produced from nonspecific interactions proteins units. As result, can accurately 13 kinds their mixtures ratios. Moreover, discriminate against diverse conformational forms. Most importantly, successfully distinguishes species, even in artificial cerebrospinal fluid samples human serum samples. This work provides attractive reliable for predicting pathologically relevant clinical diagnosis AD.

Language: Английский

Citations

2
From a Droplet to a Fibril and from a Fibril to a Droplet: Intertwined Transition Pathways in Highly Dynamic Enzyme-Modulated Peptide-Adenosine Triphosphate Systems DOI
Robert Dec, Wojciech Dzwolak, Roland Winter

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(9), P. 6045 - 6052

Published: Feb. 23, 2024

Many cellular coassemblies of proteins and polynucleotides facilitate liquid–liquid phase separation (LLPS) the subsequent self-assembly disease-associated amyloid fibrils within liquid droplets. Here, we explore dynamics coupled conformational transitions model adenosine triphosphate (ATP)-binding peptides, ACC1–13Kn, consisting potent amyloidogenic fragment insulin's A-chain (ACC1–13) merged with oligolysine segments various lengths (Kn, n = 16, 24, 40). The ATP-stabilized is preceded by LLPS for peptides sufficiently long segments. two-component droplets are in dynamic equilibria free ATP monomeric which makes them susceptible to ATP-hydrolyzing apyrase ACC1–13Kn-digesting proteinase K. Both enzymes capable rapid disassembly fibrils, producing either monomers peptide (apyrase) or released together cleaved-off (proteinase K). In latter case, enzyme-sequestered Kn form co-released ATP, resulting an unusual fibril-to-droplet transition. support highly nature aggregate-monomer equilibria, addition superstoichiometric amounts ACC1–13Kn-ATP coaggregate causes its disassembly. Our results show that droplet state not merely intermediate on pathway aggregate but may also constitute final a complex protein misfolding scenario rich degraded fragments incompetent transition again into fibrils.

Language: Английский

Citations

9
The regulation of liquid‐liquid phase separated condensates containing nucleic acids DOI Open Access
Zhuojun Dai, Xiaorong Yang

FEBS Journal, Journal Year: 2023, Volume and Issue: 291(11), P. 2320 - 2331

Published: Sept. 21, 2023

Liquid–liquid phase separation (LLPS) has been recognized as a universal biological phenomenon. It plays an important role in life activities. LLPS is induced by weak interactions between intrinsically disordered regions or low complex domains. Nucleic acids are widely present cells, and shown to be closely related LLPS. Their structure electronegativity provide the excellent platforms for formation of phase‐separated condensates. In this review, we summarize interconnected regulation nucleic demonstrated vivo vitro studies. Beside homogeneous single‐phase condensates, complicated multicompartment discussed well. Recent advances about nucleic‐acid‐induced new pathogenic mechanism drug design direction highlighted, especially virus‐mediated disease treatment prevention.

Language: Английский

Citations

17
Targeting misfolding and aggregation of the amyloid-β peptide and mutant p53 protein using multifunctional molecules DOI

Lauryn Grcic,

Grace Leech,

Kalvin Kwan

et al.

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(11), P. 1372 - 1388

Published: Jan. 1, 2024

We highlight recent advances in the development of multifunctional molecules designed to limit misfolding and aggregation intrinsically disordered biomolecules, with a focus on amyloid-beta peptide AD mutant p53 protein cancer.

Language: Английский

Citations

7
Oncogenic p53 triggers amyloid aggregation of p63 and p73 liquid droplets DOI Creative Commons
Elaine C. Petronilho, Guilherme C. de Andrade,

Gileno dos S. de Sousa

et al.

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: Sept. 16, 2024

P53 Phase separation is crucial towards amyloid aggregation and p63 p73 have enhanced expression in tumors. This study examines the phase behaviors of p53, p63, p73. Here we show that unlike DNA-binding domain p53 (p53C), p63C p73C undergo separation, but do not form amyloids under physiological temperatures. Wild-type mutant p53C droplets at 4°C aggregates 37 °C with properties. Mutant promotes amyloid-like states p73C, recruiting them into membraneless organelles. Amyloid conversion supported by thioflavin T Congo red binding, increased light scattering, circular dichroism. Full-length (or p73C) co-transfection shows reduced fluorescence recovery after photobleaching. Heparin inhibits prion-like induced p53C. These findings highlight role initiating p73, opening avenues for targeting cancer therapy.

Language: Английский

Citations

7
Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications DOI Creative Commons
Yangxin Li, Brian Liu,

Xi‐Yong Yu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 18, 2024

Abstract Once considered unconventional cellular structures, membraneless organelles (MLOs), substructures involved in biological processes or pathways under physiological conditions, have emerged as central players dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, metabolism to cancer, influence on human health disease extends widely. This review discusses underlying mechanisms LLPS, biophysical properties that drive MLO formation, their implications for We highlight recent advances understanding how physicochemical environment, molecular interactions, post-translational modifications regulate LLPS dynamics. offers an overview discovery current biomolecular condensate conditions diseases. article aims deliver latest insights by analyzing research, highlighting critical role organization. The discussion also covers membrane-associated condensates cell signaling, including those involving T-cell receptors, stress granules linked lysosomes, within Golgi apparatus. Additionally, potential targeting clinical settings is explored, promising avenues future research therapeutic interventions.

Language: Английский

Citations

6
Forkhead Box Protein K1 Promotes Chronic Kidney Disease by Driving Glycolysis in Tubular Epithelial Cells DOI Creative Commons
Lu Zhang,

Maoqing Tian,

Meng Zhang

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 31, 2024

Renal tubular epithelial cells (TECs) undergo an energy-related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of remain unclear. Herein, a new critical regulator, transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs renal fibrosis and exhibits fibrogenic metabolism-rewiring capacities reported. Genetic modification Foxk1 locus alters glycolytic metabolism fibrotic lesions. A surge expression set glycolysis-related genes following FOXK1 activation contributes shift. Nuclear-translocated forms condensate through liquid-liquid phase separation (LLPS) drive target genes. Core intrinsically disordered regions within are mapped validated. therapeutic strategy explored by targeting murine model CKD subcapsular injection recombinant adeno-associated virus 9 vector encoding Foxk1-short hairpin RNA. In summary, mechanism FOXK1-mediated TECs, which involves LLPS enhance transcriptional activity elucidated.

Language: Английский

Citations

5
Liquid-liquid phase separation in subcellular assemblages and signaling pathways: Chromatin modifications induced gene regulation for cellular physiology and functions including carcinogenesis DOI

Subhajit Chakraborty,

Jagdish Mishra,

Ankan Roy

et al.

Biochimie, Journal Year: 2024, Volume and Issue: 223, P. 74 - 97

Published: May 7, 2024

Language: Английский

Citations

4
Monoamine oxidase A probe synthesis and fluorescence imaging in cells and zebrafish based on AIE mechanism DOI
Zhengmin Yang, Tiantian Zhong,

Bingying Cao

et al.

Materials Today Chemistry, Journal Year: 2023, Volume and Issue: 35, P. 101890 - 101890

Published: Dec. 28, 2023

Language: Английский

Citations

10