Metabolites as global regulators: A new view of protein regulation

Li, Xiyan

doi:10.1002/bies.201100026

Cited by 37 publications

(15 citation statements)

References 34 publications

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“…The range of metabolites bound to the START domains from Arabidopsis PDF2 (showing activity) and GL2 (lacking activity) were overlapping but not identical, leaving the possibility that those specific to GL2 might behave as negative regulators. In general, protein–metabolite interactions may serve to: (a) activate or negatively regulate proteins, (b) stabilize protein levels, and/or (c) facilitate protein–protein interactions [35]. In addition to activating or negatively regulating transcription factor function, our experiments with the yEGFP3 fusions provide evidence that ligand-binding stabilizes protein levels of the GSV transcription factors (Additional file 1: Figure S4).…”

Section: Discussionmentioning

confidence: 90%

Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity

et al. 2014

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BackgroundSteroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains were first identified from mammalian proteins that bind lipid/sterol ligands via a hydrophobic pocket. In plants, predicted START domains are predominantly found in homeodomain leucine zipper (HD-Zip) transcription factors that are master regulators of cell-type differentiation in development. Here we utilized studies of Arabidopsis in parallel with heterologous expression of START domains in yeast to investigate the hypothesis that START domains are versatile ligand-binding motifs that can modulate transcription factor activity.ResultsOur results show that deletion of the START domain from Arabidopsis Glabra2 (GL2), a representative HD-Zip transcription factor involved in differentiation of the epidermis, results in a complete loss-of-function phenotype, although the protein is correctly localized to the nucleus. Despite low sequence similarly, the mammalian START domain from StAR can functionally replace the HD-Zip-derived START domain. Embedding the START domain within a synthetic transcription factor in yeast, we found that several mammalian START domains from StAR, MLN64 and PCTP stimulated transcription factor activity, as did START domains from two Arabidopsis HD-Zip transcription factors. Mutation of ligand-binding residues within StAR START reduced this activity, consistent with the yeast assay monitoring ligand-binding. The D182L missense mutation in StAR START was shown to affect GL2 transcription factor activity in maintenance of the leaf trichome cell fate. Analysis of in vivo protein–metabolite interactions by mass spectrometry provided direct evidence for analogous lipid-binding activity in mammalian and plant START domains in the yeast system. Structural modeling predicted similar sized ligand-binding cavities of a subset of plant START domains in comparison to mammalian counterparts.ConclusionsThe START domain is required for transcription factor activity in HD-Zip proteins from plants, although it is not strictly necessary for the protein’s nuclear localization. START domains from both mammals and plants are modular in that they can bind lipid ligands to regulate transcription factor function in a yeast system. The data provide evidence for an evolutionarily conserved mechanism by which lipid metabolites can orchestrate transcription. We propose a model in which the START domain is used by both plants and mammals to regulate transcription factor activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0070-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 90%

Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity

et al. 2014

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“…Even the SAM-independent methyl donor, folate, itself, can be methylated, which is the active form of vitamin B9 used by the human body in circulation. As it is generally thought that the number of metabolites vastly outnumbers that of proteins (Li and Snyder, 2011), metabolites could turn out to be extremely tenacious competitors for SAM, and thereby, also chromatin structures.…”

Section: Metabolite Methylation: Functions and Influence On Chromatinmentioning

confidence: 99%

Who Rules the Cell? An Epi-Tale of Histone, DNA, RNA, and the Metabolic Deep State

Leung

Gaudin

2020

Front. Plant Sci.

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Epigenetics refers to the mode of inheritance independent of mutational changes in the DNA. Early evidence has revealed methylation, acetylation, and phosphorylation of histones, as well as methylation of DNA as part of the underlying mechanisms. The recent awareness that many human diseases have in fact an epigenetic basis, due to unbalanced diets, has led to a resurgence of interest in how epigenetics might be connected with, or even controlled by, metabolism. The Next-Generation genomic technologies have now unleashed torrents of results exposing a wondrous array of metabolites that are covalently attached to selective sites on histones, DNA and RNA. Metabolites are often cofactors or targets of chromatin-modifying enzymes. Many metabolites themselves can be acetylated or methylated. This indicates that the acetylome and methylome can actually be deep and pervasive networks to ensure the nuclear activities are coordinated with the metabolic status of the cell. The discovery of novel histone marks also raises the question on the types of pathways by which their corresponding metabolites are replenished, how they are corralled to the specific histone residues and how they are recognized. Further, atypical cytosines and uracil have also been found in eukaryotic genomes. Although these new and extensive connections between metabolism and epigenetics have been established mostly in animal models, parallels must exist in plants, inasmuch as many of the basic components of chromatin and its modifying enzymes are conserved. Plants are chemical factories constantly responding to stress. Plants, therefore, should lend themselves readily for identifying new endogenous metabolites that are also modulators of nuclear activities in adapting to stress.

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“…While Recon 2 represents the ‘state of the art’ of public human metabolic network reconstructions, it should be acknowledged that it does have some known shortcomings, including the fact that a number of known metabolites and reactions (including those involving unliganded iron (Hower et al 2009; Kell 2009, 2010; Chifman et al 2012; Funke et al 2013)) have still to be included, and there are increasing numbers of ‘unexpected’ metabolite-protein reactions that are being discovered (Li et al 2010; Li and Snyder 2011; Kell 2011; Kell et al 2013). These are thus mainly ‘false negatives’ (Broadhurst and Kell 2006), and dealing with them is clearly one of the goals that will remain in any continuing curation process.…”

Section: Some Known Shortcomings Of Reconmentioning

confidence: 99%

An analysis of a ‘community-driven’ reconstruction of the human metabolic network

2013

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Following a strategy similar to that used in baker’s yeast (Herrgård et al. Nat Biotechnol 26:1155–1160, 2008). A consensus yeast metabolic network obtained from a community approach to systems biology (Herrgård et al. 2008; Dobson et al. BMC Syst Biol 4:145, 2010). Further developments towards a genome-scale metabolic model of yeast (Dobson et al. 2010; Heavner et al. BMC Syst Biol 6:55, 2012). Yeast 5—an expanded reconstruction of the Saccharomyces cerevisiae metabolic network (Heavner et al. 2012) and in Salmonella typhimurium (Thiele et al. BMC Syst Biol 5:8, 2011). A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonellatyphimurium LT2 (Thiele et al. 2011), a recent paper (Thiele et al. Nat Biotechnol 31:419–425, 2013). A community-driven global reconstruction of human metabolism (Thiele et al. 2013) described a much improved ‘community consensus’ reconstruction of the human metabolic network, called Recon 2, and the authors (that include the present ones) have made it freely available via a database at http://humanmetabolism.org/ and in SBML format at Biomodels (http://identifiers.org/biomodels.db/MODEL1109130000). This short analysis summarises the main findings, and suggests some approaches that will be able to exploit the availability of this model to advantage.

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Metabolites as global regulators: A new view of protein regulation

Cited by 37 publications

References 34 publications

Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity

Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity

Who Rules the Cell? An Epi-Tale of Histone, DNA, RNA, and the Metabolic Deep State

An analysis of a ‘community-driven’ reconstruction of the human metabolic network

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