Cleavage of 14-3-3ε by the enteroviral 3C protease dampens RIG-I-mediated antiviral signaling DOI Creative Commons
Daniel D. T. Andrews, Marli Vlok,

Dorssa Akbari Bani

et al.

Journal of Virology, Journal Year: 2023, Volume and Issue: 97(8)

Published: Aug. 9, 2023

Viruses have evolved diverse strategies to evade the host innate immune response and promote infection. The retinoic acid-inducible gene I (RIG-I)-like receptors RIG-I MDA5 are antiviral factors that sense viral RNA trigger downstream signal via mitochondrial antiviral-signaling protein (MAVS) activate type interferon expression. 14-3-3ε is a key component of translocon complex interacts with MAVS at membrane; however, exact role in this pathway not well understood. In study, we demonstrate direct substrate both poliovirus coxsackievirus B3 (CVB3) 3C proteases (3Cpro) it cleaved Q236↓G237, resulting generation N- C-terminal fragments 27.0 2.1 kDa, respectively. While exogenous expression wild-type enhances IFNB mRNA production during poly(I:C) stimulation, truncated N-terminal fragment does not. interact co-immunoprecipitation assays, nor can facilitate translocation mitochondria. Probing intrinsically disordered region identifies residues responsible for interaction between RIG-I. Finally, overexpression promotes CVB3 infection mammalian cells. strategic enterovirus 3Cpro-mediated cleavage antagonizes signaling by disrupting critical interactions within complex, thus contributing evasion response. IMPORTANCE Host work virus through various mechanisms, including known as receptor pathway. This drives molecules interferons, which necessary establish an state cellular environment. Key small chaperone 14-3-3ε, facilitates delivery sensor protein, RIG-I, show enteroviral protease cleaves infection, rendering incapable facilitating We also find dampens Our findings reveal novel strategy restricts provides insights into mechanisms underlying function signaling.

Language: Английский

Proteome-scale discovery of protein degradation and stabilization effectors DOI
Juline Poirson, Hanna Cho,

Akashdeep Dhillon

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8009), P. 878 - 886

Published: March 20, 2024

Language: Английский

Citations

25
Pervasive mislocalization of pathogenic coding variants underlying human disorders DOI
Jessica Lacoste,

Marzieh Haghighi,

Shahan Haider

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(23), P. 6725 - 6741.e13

Published: Sept. 30, 2024

Language: Английский

Citations

11
A Functional Map of the Human Intrinsically Disordered Proteome DOI Creative Commons
Iva Pritišanac, T. Reid Alderson, Đesika Kolarić

et al.

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

Published: March 17, 2024

Abstract Intrinsically disordered regions (IDRs) represent at least one-third of the human proteome and defy established structure-function paradigm. Because IDRs often have limited positional sequence conservation, functional classification using standard bioinformatics is generally not possible. Here, we show that evolutionarily conserved molecular features intrinsically (IDR-ome), termed evolutionary signatures, enable prediction IDR functions. Hierarchical clustering IDR-ome based on signatures reveals strong enrichments for frequently studied functions in transcription RNA processing, as well diverse, rarely functions, ranging from sub-cellular localization biomolecular condensates to cellular signaling, transmembrane transport, constitution cytoskeleton. We exploit information encoded within conservation propose annotations every proteome, inspect correlate with different discover co-occurring scale. Further, identify patterns proteins unknown function disease-risk genes conditions such cancer developmental disorders. Our map should be a valuable resource aids discovery new biology.

Language: Английский

Citations

10
Harnessing the 14-3-3 protein–protein interaction network DOI Creative Commons
Paulo Pitasse-Santos,

Isaac Hewitt-Richards,

Malsha D. Abeywickrama Wijewardana Sooriyaarachchi

et al.

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 86, P. 102822 - 102822

Published: April 28, 2024

Protein–protein interactions (PPIs) play a critical role in cellular signaling and represent interesting targets for therapeutic intervention. 14-3-3 proteins integrate many via PPIs are frequently implicated disease, making them intriguing drug targets. Here, we review the recent advances field. It will discuss roles within cell, elucidation of their expansive interactome, complex mechanisms that underpin function. In addition, significant development molecular glues target PPIs. particular, it focus on novel discovery methodologies have delivered selective, potent, drug-like molecules could open new avenues precision tools medicines.

Language: Английский

Citations

10
Pathogenic mutations of human phosphorylation sites affect protein–protein interactions DOI Creative Commons
Trëndelina Rrustemi, Katrina Meyer, Yvette Roske

et al.

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

Published: April 11, 2024

Abstract Despite their lack of a defined 3D structure, intrinsically disordered regions (IDRs) proteins play important biological roles. Many IDRs contain short linear motifs (SLiMs) that mediate protein-protein interactions (PPIs), which can be regulated by post-translational modifications like phosphorylation. 20% pathogenic missense mutations are found in IDRs, and understanding how such affect PPIs is essential for unraveling disease mechanisms. Here, we employ peptide-based interaction proteomics to investigate 36 disease-associated affecting phosphorylation sites. Our results unveil significant differences interactomes between phosphorylated non-phosphorylated peptides, often due disrupted phosphorylation-dependent SLiMs. We focused on mutation serine site the transcription factor GATAD1, causes dilated cardiomyopathy. find this mediates with 14-3-3 family proteins. Follow-up experiments reveal structural basis suggest binding affects GATAD1 nucleocytoplasmic transport masking nuclear localisation signal. demonstrate human sites significantly impact interactions, offering insights into potential molecular mechanisms underlying pathogenesis.

Language: Английский

Citations

9
Dynamic interactions of dimeric hub proteins underlie their diverse functions and structures: A comparative analysis of 14-3-3 and LC8 DOI Creative Commons

Jesse Howe,

Elisar Barbar

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108416 - 108416

Published: March 1, 2025

Hub proteins interact with a host of client and regulate multiple cellular functions. Dynamic hubs have single binding interface for one at time resulting in competition among clients the highest affinity. dimeric two identical sites bind either different or chains same to form homogenous complexes could also heterogeneous mixtures interconverting complexes. Here, we review interactions 14-3-3 LC8. is phosphoserine/threonine protein involved structuring regulating their phosphorylation. LC8 promoting dimerization peptides rigidification disordered regions. Both are essential genes, playing crucial role apoptosis cell cycle regulation, while critical assembly transport, DNA repair, transcription. Interestingly, both dimers can dissociate by phosphorylation, which results interactome-wide changes. Their regulated phosphorylation clients. various functions including phase separation, signaling, viral hijacking where they restrict conformational heterogeneity that nucleic acids. This comparative analysis highlights importance dynamic protein-protein diversity how small differences structures interfaces explain why primarily regulation states large

Language: Английский

Citations

1
Global organelle profiling reveals subcellular localization and remodeling at proteome scale DOI Creative Commons
Marco Y. Hein, Duo Peng, Verina Todorova

et al.

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

Published: Dec. 18, 2023

ABSTRACT Defining the subcellular distribution of all human proteins and its remodeling across cellular states remains a central goal in cell biology. Here, we present high-resolution strategy to map organization using organelle immuno-capture coupled mass spectrometry. We apply this proteomics workflow cell-wide collection membranous membrane-less compartments. A graph-based representation our data reveals localization over 7,600 proteins, defines spatial protein networks, uncovers interconnections between demonstrate that approach can be deployed comprehensively profile proteome during perturbation. By characterizing landscape following hCoV-OC43 viral infection, discover many are regulated by changes their rather than total abundance. Our results establish proteome-wide analysis provides essential insights for elucidation responses. dataset explored at organelles.czbiohub.org .

Language: Английский

Citations

19
14-3-3 binding regulates Tau assembly and microtubule association DOI Open Access
Janine Hochmair, Maxime C. M. van den Oetelaar, Lisa Diez

et al.

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

Published: March 15, 2024

Abstract 14-3-3 proteins are among the most abundant in brain and bind a large number of phosphorylation dependent manner, including prone to aggregate neurodegenerative diseases. Binding is reported facilitate function, promote solubility, coordinate assembly client proteins. For microtubule-associated protein Tau, neuronal 14-3-3, we show that phosphorylation-dependent stoichiometric binding 14-3-3ζ dimers inhibits Tau assembling into biomolecular condensates, prevents its aggregation, realizes efficient dissociation from microtubules. In contrast, at sub-stoichiometric concentrations, multivalent electrostatic interactions co-condensation with phosphorylation-independent offering an additional level regulating both These findings offer long-sought mechanistic insights how regulate substrate solubility highlight their importance for maintaining functionality brain.

Language: Английский

Citations

8
Molecular glues and induced proximity: An evolution of tools and discovery DOI

Stephanie Anne Robinson,

J Co,

Steven M. Banik

et al.

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(6), P. 1089 - 1100

Published: April 29, 2024

Language: Английский

Citations

7
Characterizing the protein–protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization DOI Creative Commons
Jake A. Ward, Beatriz Romartínez-Alonso, Danielle F. Kay

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: unknown, P. 105651 - 105651

Published: Jan. 1, 2024

Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumour suppressor protein p53. MDM2 overexpression occurs in many types cancer and results suppression wild type The 14-3-3 family adaptor proteins are known to bind 14-3-3σ isoform controls cellular localisation stability inhibit its activity. Therefore, small molecule stabilisation 14-3-3σ/MDM2 protein-protein interaction (PPI) potential therapeutic strategy for treatment cancer. Here, we provide detailed biophysical structural characterisation phosphorylation-dependent between peptides that mimic binding motifs within MDM2. data show di-phosphorylation at S166 S186 essential high affinity binary complex formed involves one di-phosphorylated peptide bound dimer 14-3-3σ. However, two phosphorylation sites do not simultaneously interact so as bridge 'multivalent' fashion. Instead, phosphorylated 'rock' grooves dimer, which unusual context proteins. In addition, amenable stabilisation. natural product fusicoccin A forms ternary with an resulting stablisation PPI. This work serves proof-of-concept drugability 14-3-3/MDM2 PPI paves way toward development more selective efficacious stabilisers.

Language: Английский

Citations

5