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1.
J Exp Bot ; 74(18): 5514-5531, 2023 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-37481465

RESUMO

Diel regulation of protein levels and protein modification had been less studied than transcript rhythms. Here, we compare transcriptome data under light-dark cycles with partial proteome and phosphoproteome data, assayed using shotgun MS, from the alga Ostreococcus tauri, the smallest free-living eukaryote. A total of 10% of quantified proteins but two-thirds of phosphoproteins were rhythmic. Mathematical modelling showed that light-stimulated protein synthesis can account for the observed clustering of protein peaks in the daytime. Prompted by night-peaking and apparently dark-stable proteins, we also tested cultures under prolonged darkness, where the proteome changed less than under the diel cycle. Among the dark-stable proteins were prasinophyte-specific sequences that were also reported to accumulate when O. tauri formed lipid droplets. In the phosphoproteome, 39% of rhythmic phospho-sites reached peak levels just before dawn. This anticipatory phosphorylation suggests that a clock-regulated phospho-dawn prepares green cells for daytime functions. Acid-directed and proline-directed protein phosphorylation sites were regulated in antiphase, implicating the clock-related casein kinases 1 and 2 in phase-specific regulation, alternating with the CMGC protein kinase family. Understanding the dynamic phosphoprotein network should be facilitated by the minimal kinome and proteome of O. tauri. The data are available from ProteomeXchange, with identifiers PXD001734, PXD001735, and PXD002909.


Assuntos
Clorófitas , Proteoma , Proteoma/metabolismo , Clorófitas/genética , Clorófitas/metabolismo , Proteínas Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Fosforilação
2.
Nat Genet ; 53(3): 304-312, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664506

RESUMO

Studying the function of common genetic variants in primary human tissues and during development is challenging. To address this, we use an efficient multiplexing strategy to differentiate 215 human induced pluripotent stem cell (iPSC) lines toward a midbrain neural fate, including dopaminergic neurons, and use single-cell RNA sequencing (scRNA-seq) to profile over 1 million cells across three differentiation time points. The proportion of neurons produced by each cell line is highly reproducible and is predictable by robust molecular markers expressed in pluripotent cells. Expression quantitative trait loci (eQTL) were characterized at different stages of neuronal development and in response to rotenone-induced oxidative stress. Of these, 1,284 eQTL colocalize with known neurological trait risk loci, and 46% are not found in the Genotype-Tissue Expression (GTEx) catalog. Our study illustrates how coupling scRNA-seq with long-term iPSC differentiation enables mechanistic studies of human trait-associated genetic variants in otherwise inaccessible cell states.


Assuntos
Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/fisiologia , Células-Tronco Pluripotentes Induzidas/citologia , Locos de Características Quantitativas , Transcriptoma , Diferenciação Celular/genética , Predisposição Genética para Doença , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurogênese/genética , Estresse Oxidativo/efeitos dos fármacos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Rotenona/toxicidade , Análise de Sequência de RNA , Análise de Célula Única
3.
Nat Genet ; 53(3): 313-321, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664507

RESUMO

Induced pluripotent stem cells (iPSCs) are an established cellular system to study the impact of genetic variants in derived cell types and developmental contexts. However, in their pluripotent state, the disease impact of genetic variants is less well known. Here, we integrate data from 1,367 human iPSC lines to comprehensively map common and rare regulatory variants in human pluripotent cells. Using this population-scale resource, we report hundreds of new colocalization events for human traits specific to iPSCs, and find increased power to identify rare regulatory variants compared with somatic tissues. Finally, we demonstrate how iPSCs enable the identification of causal genes for rare diseases.


Assuntos
Variação Genética , Células-Tronco Pluripotentes Induzidas/fisiologia , Locos de Características Quantitativas , Síndrome de Bardet-Biedl/genética , Canais de Cálcio/genética , Linhagem Celular , Ataxia Cerebelar/genética , Metilação de DNA , Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Doenças Raras/genética , Sequências Reguladoras de Ácido Nucleico , Análise de Sequência de RNA , Sequenciamento Completo do Genoma
4.
Elife ; 92020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32773033

RESUMO

Human disease phenotypes are driven primarily by alterations in protein expression and/or function. To date, relatively little is known about the variability of the human proteome in populations and how this relates to variability in mRNA expression and to disease loci. Here, we present the first comprehensive proteomic analysis of human induced pluripotent stem cells (iPSC), a key cell type for disease modelling, analysing 202 iPSC lines derived from 151 donors, with integrated transcriptome and genomic sequence data from the same lines. We characterised the major genetic and non-genetic determinants of proteome variation across iPSC lines and assessed key regulatory mechanisms affecting variation in protein abundance. We identified 654 protein quantitative trait loci (pQTLs) in iPSCs, including disease-linked variants in protein-coding sequences and variants with trans regulatory effects. These include pQTL linked to GWAS variants that cannot be detected at the mRNA level, highlighting the utility of dissecting pQTL at peptide level resolution.


Assuntos
Doença/genética , Variação Genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteoma , Transcriptoma , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Genética Populacional , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Proteômica , Locos de Características Quantitativas , RNA Mensageiro/genética , Adulto Jovem
6.
Nat Commun ; 11(1): 810, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041960

RESUMO

Recent developments in stem cell biology have enabled the study of cell fate decisions in early human development that are impossible to study in vivo. However, understanding how development varies across individuals and, in particular, the influence of common genetic variants during this process has not been characterised. Here, we exploit human iPS cell lines from 125 donors, a pooled experimental design, and single-cell RNA-sequencing to study population variation of endoderm differentiation. We identify molecular markers that are predictive of differentiation efficiency of individual lines, and utilise heterogeneity in the genetic background across individuals to map hundreds of expression quantitative trait loci that influence expression dynamically during differentiation and across cellular contexts.


Assuntos
Diferenciação Celular/genética , Expressão Gênica/genética , Células-Tronco Pluripotentes Induzidas/citologia , Linhagem Celular , Endoderma/citologia , Feminino , Perfilação da Expressão Gênica , Interação Gene-Ambiente , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Masculino , Locos de Características Quantitativas , Análise de Célula Única
7.
In Silico Plants ; 1(1)2019.
Artigo em Inglês | MEDLINE | ID: mdl-36203490

RESUMO

We assessed mechanistic temperature influence on flowering by incorporating temperature-responsive flowering mechanisms across developmental age into an existing model. Temperature influences the leaf production rate as well as expression of FLOWERING LOCUS T (FT), a photoperiodic flowering regulator that is expressed in leaves. The Arabidopsis Framework Model incorporated temperature influence on leaf growth but ignored the consequences of leaf growth on and direct temperature influence of FT expression. We measured FT production in differently aged leaves and modified the model, adding mechanistic temperature influence on FT transcription, and causing whole-plant FT to accumulate with leaf growth. Our simulations suggest that in long days, the developmental stage (leaf number) at which the reproductive transition occurs is influenced by day length and temperature through FT, while temperature influences the rate of leaf production and the time (in days) the transition occurs. Further, we demonstrate that FT is mainly produced in the first 10 leaves in the Columbia (Col-0) accession, and that FT accumulation alone cannot explain flowering in conditions in which flowering is delayed. Our simulations supported our hypotheses that: (i) temperature regulation of FT, accumulated with leaf growth, is a component of thermal time, and (ii) incorporating mechanistic temperature regulation of FT can improve model predictions when temperatures change over time.

8.
Proc Natl Acad Sci U S A ; 115(41): 10523-10528, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30254157

RESUMO

In plants, light receptors play a pivotal role in photoperiod sensing, enabling them to track seasonal progression. Photoperiod sensing arises from an interaction between the plant's endogenous circadian oscillator and external light cues. Here, we characterize the role of phytochrome A (phyA) in photoperiod sensing. Our metaanalysis of functional genomic datasets identified phyA as a principal regulator of morning-activated genes, specifically in short photoperiods. We demonstrate that PHYA expression is under the direct control of the PHYTOCHROME INTERACTING FACTOR transcription factors, PIF4 and PIF5. As a result, phyA protein accumulates during the night, especially in short photoperiods. At dawn, phyA activation by light results in a burst of gene expression, with consequences for physiological processes such as anthocyanin accumulation. The combination of complex regulation of PHYA transcript and the unique molecular properties of phyA protein make this pathway a sensitive detector of both dawn and photoperiod.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Ritmo Circadiano , Fotoperíodo , Fitocromo A/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Antocianinas/metabolismo , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Luz , Fitocromo A/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/crescimento & desenvolvimento
9.
Mol Syst Biol ; 14(3): e7962, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29496885

RESUMO

Plants respond to seasonal cues such as the photoperiod, to adapt to current conditions and to prepare for environmental changes in the season to come. To assess photoperiodic responses at the protein level, we quantified the proteome of the model plant Arabidopsis thaliana by mass spectrometry across four photoperiods. This revealed coordinated changes of abundance in proteins of photosynthesis, primary and secondary metabolism, including pigment biosynthesis, consistent with higher metabolic activity in long photoperiods. Higher translation rates in the day than the night likely contribute to these changes, via an interaction with rhythmic changes in RNA abundance. Photoperiodic control of protein levels might be greatest only if high translation rates coincide with high transcript levels in some photoperiods. We term this proposed mechanism "translational coincidence", mathematically model its components, and demonstrate its effect on the Arabidopsis proteome. Datasets from a green alga and a cyanobacterium suggest that translational coincidence contributes to seasonal control of the proteome in many phototrophic organisms. This may explain why many transcripts but not their cognate proteins exhibit diurnal rhythms.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Fotoperíodo , Biossíntese de Proteínas , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Ritmo Circadiano , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Espectrometria de Massas , Modelos Teóricos , Proteômica
10.
Methods Mol Biol ; 1629: 317-330, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28623594

RESUMO

Transcriptional regulatory circuits are often complex, consisting of many components and regulatory interactions. Mathematical modeling is an important tool for understanding the behavior of these circuits, and identifying gaps in our understanding of gene regulation. Ordinary differential equations (ODEs) are a commonly used formalism for constructing mathematical models of complex regulatory networks. Here, I outline the steps involved in developing, parameterizing, and testing an ODE model of a gene regulatory network.


Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Modelos Teóricos , Algoritmos , Arabidopsis/genética , Simulação por Computador , Reprodutibilidade dos Testes , Biologia de Sistemas/métodos
11.
Proc Natl Acad Sci U S A ; 113(27): 7667-72, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27330114

RESUMO

Plants sense the light environment through an ensemble of photoreceptors. Members of the phytochrome class of light receptors are known to play a critical role in seedling establishment, and are among the best-characterized plant signaling components. Phytochromes also regulate adult plant growth; however, our knowledge of this process is rather fragmented. This study demonstrates that phytochrome controls carbon allocation and biomass production in the developing plant. Phytochrome mutants have a reduced CO2 uptake, yet overaccumulate daytime sucrose and starch. This finding suggests that even though carbon fixation is impeded, the available carbon resources are not fully used for growth during the day. Supporting this notion, phytochrome depletion alters the proportion of day:night growth. In addition, phytochrome loss leads to sizeable reductions in overall growth, dry weight, total protein levels, and the expression of CELLULOSE SYNTHASE-LIKE genes. Because cellulose and protein are major constituents of plant biomass, our data point to an important role for phytochrome in regulating these fundamental components of plant productivity. We show that phytochrome loss impacts core metabolism, leading to elevated levels of tricarboxylic acid cycle intermediates, amino acids, sugar derivatives, and notably the stress metabolites proline and raffinose. Furthermore, the already growth-retarded phytochrome mutants are less responsive to growth-inhibiting abiotic stresses and have elevated expression of stress marker genes. This coordinated response appears to divert resources from energetically costly biomass production to improve resilience. In nature, this strategy may be activated in phytochrome-disabling, vegetation-dense habitats to enhance survival in potentially resource-limiting conditions.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Fitocromo/fisiologia , Arabidopsis/genética , Arabidopsis/metabolismo , Metabolismo dos Carboidratos , Dióxido de Carbono/metabolismo , Estresse Fisiológico
12.
Plant Cell Environ ; 39(9): 1955-81, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27075884

RESUMO

Plants use the circadian clock to sense photoperiod length. Seasonal responses like flowering are triggered at a critical photoperiod when a light-sensitive clock output coincides with light or darkness. However, many metabolic processes, like starch turnover, and growth respond progressively to photoperiod duration. We first tested the photoperiod response of 10 core clock genes and two output genes. qRT-PCR analyses of transcript abundance under 6, 8, 12 and 18 h photoperiods revealed 1-4 h earlier peak times under short photoperiods and detailed changes like rising PRR7 expression before dawn. Clock models recapitulated most of these changes. We explored the consequences for global gene expression by performing transcript profiling in 4, 6, 8, 12 and 18 h photoperiods. There were major changes in transcript abundance at dawn, which were as large as those between dawn and dusk in a given photoperiod. Contributing factors included altered timing of the clock relative to dawn, light signalling and changes in carbon availability at night as a result of clock-dependent regulation of starch degradation. Their interaction facilitates coordinated transcriptional regulation of key processes like starch turnover, anthocyanin, flavonoid and glucosinolate biosynthesis and protein synthesis and underpins the response of metabolism and growth to photoperiod.


Assuntos
Arabidopsis/fisiologia , Relógios Circadianos/genética , Genes de Plantas , Fotoperíodo , Proteínas de Arabidopsis/metabolismo , Metabolismo dos Carboidratos , Modelos Biológicos , Análise de Componente Principal , Proteínas Serina-Treonina Quinases/metabolismo , Metabolismo Secundário , Amido/biossíntese , Sacarose/metabolismo , Transcriptoma
13.
PLoS Comput Biol ; 12(1): e1004604, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26741131

RESUMO

Cell cycle progression is carefully coordinated with a cell's intra- and extracellular environment. While some pathways have been identified that communicate information from the environment to the cell cycle, a systematic understanding of how this information is dynamically processed is lacking. We address this by performing dynamic sensitivity analysis of three mathematical models of the cell cycle in Saccharomyces cerevisiae. We demonstrate that these models make broadly consistent qualitative predictions about cell cycle progression under dynamically changing conditions. For example, it is shown that the models predict anticorrelated changes in cell size and cell cycle duration under different environments independently of the growth rate. This prediction is validated by comparison to available literature data. Other consistent patterns emerge, such as widespread nonmonotonic changes in cell size down generations in response to parameter changes. We extend our analysis by investigating glucose signalling to the cell cycle, showing that known regulation of Cln3 translation and Cln1,2 transcription by glucose is sufficient to explain the experimentally observed changes in cell cycle dynamics at different glucose concentrations. Together, these results provide a framework for understanding the complex responses the cell cycle is capable of producing in response to dynamic environments.


Assuntos
Ciclo Celular/fisiologia , Modelos Biológicos , Transdução de Sinais/fisiologia , Biologia de Sistemas/métodos , Glucose/metabolismo , Saccharomyces cerevisiae/metabolismo
14.
Open Biol ; 5(10)2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26468131

RESUMO

Our understanding of the complex, transcriptional feedback loops in the circadian clock mechanism has depended upon quantitative, timeseries data from disparate sources. We measure clock gene RNA profiles in Arabidopsis thaliana seedlings, grown with or without exogenous sucrose, or in soil-grown plants and in wild-type and mutant backgrounds. The RNA profiles were strikingly robust across the experimental conditions, so current mathematical models are likely to be broadly applicable in leaf tissue. In addition to providing reference data, unexpected behaviours included co-expression of PRR9 and ELF4, and regulation of PRR5 by GI. Absolute RNA quantification revealed low levels of PRR9 transcripts (peak approx. 50 copies cell(-1)) compared with other clock genes, and threefold higher levels of LHY RNA (more than 1500 copies cell(-1)) than of its close relative CCA1. The data are disseminated from BioDare, an online repository for focused timeseries data, which is expected to benefit mechanistic modelling. One data subset successfully constrained clock gene expression in a complex model, using publicly available software on parallel computers, without expert tuning or programming. We outline the empirical and mathematical justification for data aggregation in understanding highly interconnected, dynamic networks such as the clock, and the observed design constraints on the resources required to make this approach widely accessible.


Assuntos
Arabidopsis/fisiologia , Proteínas CLOCK/genética , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/biossíntese , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Relógios Biológicos/genética , Ritmo Circadiano/genética , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Retroalimentação Fisiológica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/genética , Redes Reguladoras de Genes/genética , RNA Mensageiro/genética , Sacarose/metabolismo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
15.
Mol Syst Biol ; 11(1): 776, 2015 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-25600997

RESUMO

Clock-regulated pathways coordinate the response of many developmental processes to changes in photoperiod and temperature. We model two of the best-understood clock output pathways in Arabidopsis, which control key regulators of flowering and elongation growth. In flowering, the model predicted regulatory links from the clock to cycling DOF factor 1 (CDF1) and flavin-binding, KELCH repeat, F-box 1 (FKF1) transcription. Physical interaction data support these links, which create threefold feed-forward motifs from two clock components to the floral regulator FT. In hypocotyl growth, the model described clock-regulated transcription of phytochrome-interacting factor 4 and 5 (PIF4, PIF5), interacting with post-translational regulation of PIF proteins by phytochrome B (phyB) and other light-activated pathways. The model predicted bimodal and end-of-day PIF activity profiles that are observed across hundreds of PIF-regulated target genes. In the response to temperature, warmth-enhanced PIF4 activity explained the observed hypocotyl growth dynamics but additional, temperature-dependent regulators were implicated in the flowering response. Integrating these two pathways with the clock model highlights the molecular mechanisms that coordinate plant development across changing conditions.


Assuntos
Arabidopsis/genética , Ritmo Circadiano , Flores/fisiologia , Hipocótilo/crescimento & desenvolvimento , Fotoperíodo , RNA de Plantas/isolamento & purificação , Temperatura , Arabidopsis/fisiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Relógios Circadianos/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica de Plantas , Luz , Fitocromo B/genética , Fitocromo B/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Plantas/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
Plant Cell ; 26(1): 5-20, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24481073

RESUMO

Plants respond to changes in the environment by triggering a suite of regulatory networks that control and synchronize molecular signaling in different tissues, organs, and the whole plant. Molecular studies through genetic and environmental perturbations, particularly in the model plant Arabidopsis thaliana, have revealed many of the mechanisms by which these responses are actuated. In recent years, mathematical modeling has become a complementary tool to the experimental approach that has furthered our understanding of biological mechanisms. In this review, we present modeling examples encompassing a range of different biological processes, in particular those regulated by light. Current issues and future directions in the modeling of plant systems are discussed.


Assuntos
Arabidopsis/fisiologia , Modelos Biológicos , Transdução de Sinais , Arabidopsis/metabolismo , Arabidopsis/efeitos da radiação , Ritmo Circadiano , Fotoperíodo , Fitocromo/metabolismo , Fitocromo/fisiologia
17.
J R Soc Interface ; 11(91): 20130979, 2014 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-24335560

RESUMO

In many plants, starch is synthesized during the day and degraded during the night to avoid carbohydrate starvation in darkness. The circadian clock participates in a dynamic adjustment of starch turnover to changing environmental condition through unknown mechanisms. We used mathematical modelling to explore the possible scenarios for the control of starch turnover by the molecular components of the plant circadian clock. Several classes of plausible models were capable of describing the starch dynamics observed in a range of clock mutant plants and light conditions, including discriminating circadian protocols. Three example models of these classes are studied in detail, differing in several important ways. First, the clock components directly responsible for regulating starch degradation are different in each model. Second, the intermediate species in the pathway may play either an activating or inhibiting role on starch degradation. Third, the system may include a light-dependent interaction between the clock and downstream processes. Finally, the clock may be involved in the regulation of starch synthesis. We discuss the differences among the models' predictions for diel starch profiles and the properties of the circadian regulators. These suggest additional experiments to elucidate the pathway structure, avoid confounding results and identify the molecular components involved.


Assuntos
Arabidopsis/metabolismo , Metabolismo dos Carboidratos , Ritmo Circadiano , Amido/metabolismo , Proteínas de Arabidopsis/metabolismo , Relógios Biológicos , Simulação por Computador , Retroalimentação Fisiológica , Regulação da Expressão Gênica de Plantas , Cinética , Luz , Modelos Teóricos , Mutação , Fotoperíodo , Transdução de Sinais , Biologia de Sistemas
18.
BMC Syst Biol ; 5: 103, 2011 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-21714894

RESUMO

BACKGROUND: The coupling of pathways and processes through shared components is being increasingly recognised as a common theme which occurs in many cell signalling contexts, in which it plays highly non-trivial roles. RESULTS: In this paper we develop a basic modelling and systems framework in a general setting for understanding the coupling of processes and pathways through shared components. Our modelling framework starts with the interaction of two components with a common third component and includes production and degradation of all these components. We analyze the signal processing in our model to elucidate different aspects of the coupling. We show how different kinds of responses, including "ultrasensitive" and adaptive responses, may occur in this setting. We then build on the basic model structure and examine the effects of additional control regulation, switch-like signal processing, and spatial signalling. In the process, we identify a way in which allosteric regulation may contribute to signalling specificity, and how competitive effects may allow an enzyme to robustly coordinate and time the activation of parallel pathways. CONCLUSIONS: We have developed and analyzed a common systems platform for examining the effects of coupling of processes through shared components. This can be the basis for subsequent expansion and understanding the many biologically observed variations on this common theme.


Assuntos
Regulação Alostérica/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Biológicos , Transdução de Sinais/fisiologia , Simulação por Computador
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