Ubiquitous purine sensor modulates diverse signal transduction pathways in bacteria DOI Creative Commons
Tino Krell, Elizabet Monteagudo‐Cascales, Vadim M. Gumerov

et al.

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 16, 2023

Abstract Purines and their derivatives are key molecules for controlling intracellular energy homeostasis nucleotide synthesis. In eukaryotes, including humans, purines also act as signaling that mediate extracellular communication control cellular processes, such proliferation, migration, differentiation, apoptosis. However, the role of in bacteria is largely unknown. Here, by combining structural sequence information, we define a purine-binding motif, which present sensor domains thousands bacterial receptors modulate motility, gene expression, metabolism second messenger turnover. The screening compound libraries microcalorimetric titrations selected validated ability to specifically bind purine derivatives. physiological relevance sensing was demonstrated system modulates c-di-GMP levels.

Language: Английский

Bacterial sensor evolved by decreasing complexity DOI Creative Commons
Elizabet Monteagudo‐Cascales, J.A. Gavira, Jiawei Xing

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(5)

Published: Jan. 29, 2025

Bacterial receptors feed into multiple signal transduction pathways that regulate a variety of cellular processes including gene expression, second messenger levels, and motility. Receptors are typically activated by binding to ligand-binding domains (LBDs). Cache omnipresent LBDs found in bacteria, archaea, eukaryotes, humans. They form the predominant family extracytosolic bacterial were identified all major receptor types. composed either single (sCache) or double (dCache) structural module. The functional relevance bimodular remains poorly understood. Here, we identify PacF chemoreceptor phytopathogen Pectobacterium atrosepticum recognizes formate at membrane-distal module its dCache domain, triggering chemoattraction. We further demonstrate formate-specific sCache has evolved from exemplified PacF, losing membrane-proximal By solving high-resolution structures two members complex with formate, show molecular basis for is highly similar, despite their low sequence identity. apparent loss may be related observation bind ligands module, whereas studies have failed find bound This work advances our understanding sensing suggests evolution reducing complexity route shaping diversity.

Language: Английский

Citations

2
MiST 4.0: a new release of the microbial signal transduction database, now with a metagenomic component DOI Creative Commons
Vadim M. Gumerov,

Luke E. Ulrich,

Igor B. Zhulin

et al.

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 52(D1), P. D647 - D653

Published: Oct. 4, 2023

Abstract Signal transduction systems in bacteria and archaea link environmental stimuli to specific adaptive cellular responses. They control gene expression, motility, biofilm formation, development other processes that are vital survival. The microbial signal (MiST) database is an online resource stores tens of thousands genomes allows users explore their profiles, analyze bulk using the application programming interface (API) make testable hypotheses about functions newly identified signaling systems. However, metagenomes remained completely unexplored. To lay foundation for research metagenomic transduction, we have prepared a new release MiST database, 4.0, which features over 10 000 metagenome-assembled (MAGs), scaled representation proteins detailed BioSample information. In addition, several been processed stored database. A has developed seamlessly switch between MAGs. 4.0 freely available at https://mistdb.com; MAGs can also be explored API on same page.

Language: Английский

Citations

33
Ubiquitous purine sensor modulates diverse signal transduction pathways in bacteria DOI Creative Commons
Elizabet Monteagudo‐Cascales, Vadim M. Gumerov, Matilde Fernández

et al.

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

Published: July 12, 2024

Abstract Purines and their derivatives control intracellular energy homeostasis nucleotide synthesis, act as signaling molecules. Here, we combine structural sequence information to define a purine-binding motif that is present in sensor domains of thousands bacterial receptors modulate motility, gene expression, metabolism, second-messenger turnover. Microcalorimetric titrations selected validate ability specifically bind purine derivatives, evolutionary analyses indicate sensors share common ancestor with amino-acid receptors. Furthermore, provide experimental evidence physiological relevance sensing system modulates c-di-GMP levels.

Language: Английский

Citations

8
Framework for exploring the sensory repertoire of the human gut microbiota DOI Creative Commons

Patricia A. Ross,

Wenhao Xu, Ekaterina Jalomo-Khayrova

et al.

mBio, Journal Year: 2024, Volume and Issue: 15(6)

Published: May 17, 2024

ABSTRACT Bacteria sense changes in their environment and transduce signals to adjust cellular functions accordingly. For this purpose, bacteria employ various sensors feeding into multiple signal transduction pathways. Signal recognition by bacterial is studied mainly a few model organisms, but advances genome sequencing analysis offer new ways of exploring the sensory repertoire many understudied organisms. The human gut natural target line study: it nutrient-rich dynamic home thousands species whose activities impact health. Many commensals are also poorly compared organisms known through sequences. To begin respond to, we have designed framework that enables identification domains, prediction they recognize, experimental verification these predictions. We validate framework’s functionality systematically identifying amino acid selected genomes metagenomes, characterizing binding properties, demonstrating potential. IMPORTANCE central process governing how environment. complex with living fluctuating streams nutrients. One inhabitant, Escherichia coli , organism for studying transduction. However, E. not representative most microbes, signaling pathways other comprising microbiota remain understood. This work provides foundation explore recognized

Language: Английский

Citations

5
Structural assembly of the PAS domain drives the catalytic activation of metazoan PASK DOI Creative Commons
Sajina Dhungel, Michael Xiao,

Rajesh Rajaian Pushpabai

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(12)

Published: March 19, 2025

PAS domains are ubiquitous sensory modules that transduce environmental signals into cellular responses through tandem folds and PAS-associated C-terminal (PAC) motifs. While this conserved architecture underpins their regulatory roles, here we uncover a structural divergence in the metazoan domain-regulated kinase (PASK). By integrating evolutionary-scale domain mapping with deep learning-based models, identified two PASK, namely PAS-B PAS-C, addition to previously known PAS-A domain. Unlike canonical domains, fold PAC motif PAS-C spatially segregated by an unstructured linker, yet functional module is assembled intramolecular interactions. We demonstrate assembly nutrient responsive serves remodel quaternary structure of PASK positions near activation loop. This nutrient-sensitive spatial arrangement stabilizes loop, enabling catalytic PASK. These findings revealed alternative mode control proteins, where links sensing enzymatic activity. demonstrating integrate dynamic rearrangements, study broadens understanding roles highlights potential opportunities for targeting domain-mediated pathways therapeutic applications.

Language: Английский

Citations

0
Structural and functional diversity of sensor domains in bacterial transmembrane receptors DOI
Miguel A. Matilla, J.A. Gavira, Elizabet Monteagudo‐Cascales

et al.

Trends in Microbiology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Pathogenic KCNH2-G53S variant in the PAS domain influences the electrophysiological phenotype in long QT syndrome type 2 DOI Creative Commons
Dasom Mun, Jiyoung Kang,

Malgeum Park

et al.

Frontiers in Cardiovascular Medicine, Journal Year: 2025, Volume and Issue: 12

Published: April 9, 2025

Long QT syndrome type 2 (LQT2) is an arrythmia caused by loss-of-function mutations in KCNH2, leading to impaired Kv11.1 channel function. To better understand LQT2, we examined the electrophysiological differences related G53S variant, which located within PAS domain of using patient-specific human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs). We generated hiPSC-CMs from a patient harboring KCNH2G53S variant and healthy control non-integrative Sendai virus-mediated reprogramming. Their properties were assessed microelectrode arrays (MEA), Ca2+ dynamics characterized Fluo-4 dye. The experienced aborted sudden cardiac death at 22 years age, was diagnosed with LQT, had implantable cardioverter-defibrillator (ICD) implanted. expressed less KCNH2 than normal CMs. Transcriptomic analysis revealed 3,857 differentially genes, highlighting significant changes pathways LQT2 development. Action potential duration significantly longer (545.3 ± 176.3 ms vs. 339.9 44.5 ms; P = 0.019). Corrected field (318.0 66.3 234.5 21.0 0.015), indicating altered electrophysiology. exhibited increased calcium transient amplitude prolonged wave under isoproterenol stimulation, exacerbated abnormal handling. Our carrying heterozygous mutation, showed electrophysiology handling, provides basis for developing improved management strategies patients LQT2.

Language: Английский

Citations

0
Small amounts of misassembly can have disproportionate effects on pangenome-based metagenomic analyses DOI Creative Commons

Stephanie N. Majernik,

Larry Beaver,

Patrick H. Bradley

et al.

mSphere, Journal Year: 2025, Volume and Issue: unknown

Published: April 29, 2025

ABSTRACT Individual genes from microbiomes can drive host-level phenotypes. To help identify such candidate genes, several recent tools estimate microbial gene copy numbers directly metagenomes. These rely on alignments to pangenomes, which, in turn, are derived the set of all individual genomes one species. While large-scale metagenomic assembly efforts have made pangenome estimates more complete, mixed communities also introduce contamination into assemblies, and it is unknown how robust pangenome-based analyses these errors. gain insight this problem, we re-analyzed a case-control study gut microbiome cirrhosis, focusing commensal Clostridia previously implicated disease. We tested for differentially prevalent Lachnospiraceae then investigated which were likely be contaminants using sequence similarity searches. Out 86 found that 33 (38%) probably originating taxa as Veillonella Haemophilus , unrelated genera independently correlated with disease status. Our results demonstrate even small amounts metagenome below typical quality thresholds, threaten overwhelm gene-level analyses. However, show accurately identified method based gene-to-species correlation. After removing contaminants, observe flagellar motility clusters Lachnospira eligens associated cirrhosis integrated our an analysis visualization pipeline, PanSweep, automatically cases where may bias gene-resolved IMPORTANCE Metagenome-assembled genomes, or MAGs, constructed without pure cultures microbes. Large-scale build MAGs yielded complete pangenomes (i.e., sets species). Pangenomes allow us measure strain variation content, strongly affect phenotype. because come communities, they contaminate DNA; much impacts downstream has not been studied. Using microbes test case, investigate affects content. Surprisingly, small, MAG (<5%) result disproportionately high levels false positive associations (38%). Fortunately, most flagged provide simple doing so. Furthermore, applying reveals new association between motility.

Language: Английский

Citations

0
Conserved and Unique Roles of bHLH-PAS Transcription Factors in Insects – From Clock to Hormone Reception DOI Creative Commons
Sarka Tumova, David Doležel, Marek Jindra

et al.

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 436(3), P. 168332 - 168332

Published: Oct. 29, 2023

A dozen bHLH-PAS transcription factors have evolved since the dawn of animal kingdom; nine them mutual orthologs between arthropods and vertebrates. These proteins are master regulators in a range developmental processes from organogenesis, nervous system formation functioning, to cell fate decisions defining identity limbs or photoreceptors for color vision. Among functionally best conserved acting circadian clock. On other side spectrum fundamental physiological mechanisms such as those underlying xenobiotic detoxification, oxygen homeostasis, metabolic adaptation hypoxia, infection tumor progression. Predictably, malfunctioning leads pathologies. Performance individual is modulated at multiple levels including dimerization protein–protein interactions, proteasomal degradation, by binding low-molecular weight ligands. Despite vast evolutionary gap dividing vertebrates, differences their anatomy, many functions orthologous remarkably similar, molecular level. Our phylogenetic analysis shows that one protein type has been lost during vertebrate evolution. This unique function receptor sesquiterpenoid juvenile hormones insects crustaceans. Although some regulated small molecules, hormone presents an unprecedented case, all non-peptide activate members nuclear family. The purpose this review compare highlight parallels functioning

Language: Английский

Citations

7
Unpacking Alternative Features of the Bacterial Chemotaxis System DOI
Alise R. Muok, F.A. Olsthoorn, Ariane Briegel

et al.

Annual Review of Microbiology, Journal Year: 2024, Volume and Issue: 78(1), P. 169 - 189

Published: July 10, 2024

The bacterial chemotaxis system is one of the best-understood cellular pathways and serves as model for signal transduction systems. Most research has been conducted with transmembrane systems from Escherichia coli established paradigms that were thought to be universal. However, emerging revealed many bacteria possess alternative features their system, demonstrating these are likely more complex than previously assumed. Here, we compare canonical E. diverge in supramolecular architecture, sensory mechanisms, protein composition. have evolved accommodate chemical specificities natural niches cell morphologies. Collectively, studies demonstrate a rapidly expanding field offers new opportunities explore this exceedingly diverse system.

Language: Английский

Citations

2