Rwdd1, a Thymus Aging Related Molecule, Is a New Member of the Intrinsically Unstructured Protein Family

Kang, Ning; Dai, Caili; Wang, Li; Duan, Lian; Liu, Shirong; Tang, Long; Li, Qingfeng; Cui, Lianxian; Wang, He

doi:10.1038/cmi.2008.41

Cited by 11 publications

(4 citation statements)

References 15 publications

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“…As found for Yih1/IMPACT, Gir2 associates with Gcn1 via an N‐terminal RWD domain and inhibits Gcn2 activation when overexpressed; interestingly it also associates with the ribosome [20]. Human Gir2 orthologues were identified [28], again demonstrating the high evolutionary conservation of a regulatory protein involved in controlling Gcn2, and simultaneously underscoring the fact that yeast can be used as model system for fully understanding the molecular mechanisms underlying the regulation of Gcn2.…”

Section: Discussionmentioning

confidence: 92%

Evidence that Yih1 resides in a complex with ribosomes

2012

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Adjusting protein synthesis by phosphorylating eukaryotic translation initiation factor 2 (eIF2α) is a major mechanism by which eukaryotes adapt to and overcome stress. The eIF2α kinase Gcn2 is essential for overcoming amino acid starvation in all eukaryotes. We have shown that to sense starvation, the Gcn2 RWD domain must directly contact its effector protein, Gcn1, and both must bind to the ribosome, suggesting that starvation is sensed within a Gcn1–Gcn2–ribosome complex. The mammalian protein IMPACT, highly expressed in neurons, and its yeast orthologue yeast IMPACT homologue (Yih1) harbour an RWD domain with Gcn1‐binding activity. We have shown that Yih1 downregulates Gcn2 by competing with Gcn2 for Gcn1‐binding. Here, we provide evidence that Yih1 forms a complex with ribosomes. In velocity sedimentation assays, overexpressed glutathione S‐transferase (GST)‐tagged Yih1 cosedimented with polyribosomes independently of Gcn1. Reduction of polyribosomes to monosomes concomitantly decreased GST–Yih1 sedimentation in the heavy fractions where polyribosomes are normally found. Furthermore, GST–Yih1 coprecipitated large ribosomal protein Rpl39 independently of Gcn1. GST–Yih1 overexpression did not significantly affect Gcn1–ribosome or Gcn2–ribosome cosedimentation. myc‐tagged Yih1 expressed from its own promoter cosedimented with polyribosomes independently of Gcn1, indicating that Yih1–ribosome interaction occurs under physiological conditions. GST–IMPACT cosedimented with yeast ribosomes and coprecipitated Rpl39 in a Gcn1‐independent fashion, suggesting that Yih1/IMPACT–ribosome association is evolutionarily conserved. Moreover, GST–IMPACT coprecipitated actin as found for GST–Yih1. Taken together, our findings strongly suggest that IMPACT/Yih1 associates with ribosomes and that these ribosomes may simultaneously carry Gcn1 and Gcn2. Close physical proximity of Yih1 to the Gcn1–Gcn2–ribosome complex would allow cells to quickly inhibit Gcn2 whenever or wherever necessary. Structured digital abstract Polyribosomes physically interact with http://www.uniprot.org/uniprot/P25637, http://www.uniprot.org/uniprot/P33892, http://www.uniprot.org/uniprot/P15442, http://www.uniprot.org/uniprot/P16521, http://www.uniprot.org/uniprot/P02994, http://www.uniprot.org/uniprot/Q03768, http://www.uniprot.org/uniprot/P04650, RPS22, by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0030assays (http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8309449) http://www.uniprot.org/uniprot/P25637 http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0915 with http://www.uniprot.org/uniprot/P04650 by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0030 (http://mint.bio.uniroma2.it/mint/search/interaction.do?interactionAc=MINT-8309485) http://www.uniprot.org/uniprot/O55091 http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0914 with http://www.uniprot.org/uniprot/P33892, actin, RPS22 and http://www.uniprot.org/uniprot/P04650 by http://www.ebi.ac.uk/ontology-lookup/?termId=MI:0096 (http://mint.bio.uniroma2.it/mint/search/in...

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Section: Discussionmentioning

confidence: 92%

Evidence that Yih1 resides in a complex with ribosomes

2012

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“…Within the upland breeds, many genes found in the selected regions had functions related to cell stress and metabolism (Table 3). The most highly supported by DCMS, RWDD1, encodes a transcription factor related to sulfide metabolism in metozoans (Kang et al, 2008;Li et al, 2018). HSPA5 also responds to cell stress mechanisms by promoting protein refolding in the endoplasmic reticulum in cancers or virally-infected cells (Booth et al, 2015).…”

Section: Candidate Genes In Welsh Upland Sheep Breedsmentioning

confidence: 99%

Genotyping and Whole-Genome Resequencing of Welsh Sheep Breeds Reveal Candidate Genes and Variants for Adaptation to Local Environment and Socioeconomic Traits

et al. 2021

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BackgroundAdvances in genetic tools applied to livestock breeding has prompted research into the previously neglected breeds adapted to harsh local environments. One such group is the Welsh mountain sheep breeds, which can be farmed at altitudes of 300 m above sea level but are considered to have a low productive value because of their poor wool quality and small carcass size. This is contrary to the lowland breeds which are more suited to wool and meat production qualities, but do not fare well on upland pasture. Herein, medium-density genotyping data from 317 individuals representing 15 Welsh sheep breeds were used alongside the whole-genome resequencing data of 14 breeds from the same set to scan for the signatures of selection and candidate genetic variants using haplotype- and SNP-based approaches.ResultsHaplotype-based selection scan performed on the genotyping data pointed to a strong selection in the regions of GBA3, PPARGC1A, APOB, and PPP1R16B genes in the upland breeds, and RNF24, PANK2, and MUC15 in the lowland breeds. SNP-based selection scan performed on the resequencing data pointed to the missense mutations under putative selection relating to a local adaptation in the upland breeds with functions such as angiogenesis (VASH1), anti-oxidation (RWDD1), cell stress (HSPA5), membrane transport (ABCA13 and SLC22A7), and insulin signaling (PTPN1 and GIGFY1). By contrast, genes containing candidate missense mutations in the lowland breeds are related to cell cycle (CDK5RAP2), cell adhesion (CDHR3), and coat color (MC1R).ConclusionWe found new variants in genes with potentially functional consequences to the adaptation of local sheep to their environments in Wales. Knowledge of these variations is important for improving the adaptative qualities of UK and world sheep breeds through a marker-assisted selection.

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“…Therefore, we speculate that DRG2 associates with mRNA and thereby plays roles in transcription, mRNA splicing, and translation. RWDD1, which is known to interact with DRG2, was reported to interact with androgen receptors and to act as a coactivator of androgen-dependent transcription [28][29][30]. If RWDD1 can function as a coactivator of other nuclear receptors including ERα/β, it would raise the possibility that DRG2 and RWDD1 function cooperatively in the transcription of ERα target genes.…”

Section: Possible Functions Of Drg2 and Rwdd1 In Regulating Epigeneticsmentioning

confidence: 99%

Developmentally regulated GTP binding protein 2 (DRG2) and Nup107 are associated with epigenetic regulation via H2A.Z on promoter regions of specific genes in MCF7 breast cancer cells

Tanabe¹,

Fujiyama²,

Horimoto³

2016

J Clin Epigenet

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Rwdd1, a Thymus Aging Related Molecule, Is a New Member of the Intrinsically Unstructured Protein Family

Cited by 11 publications

References 15 publications

Evidence that Yih1 resides in a complex with ribosomes

Evidence that Yih1 resides in a complex with ribosomes

Genotyping and Whole-Genome Resequencing of Welsh Sheep Breeds Reveal Candidate Genes and Variants for Adaptation to Local Environment and Socioeconomic Traits

Developmentally regulated GTP binding protein 2 (DRG2) and Nup107 are associated with epigenetic regulation via H2A.Z on promoter regions of specific genes in MCF7 breast cancer cells

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