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Proteomic and genomic characterization of a yeast model for Ogden syndrome [RNA-seq and Ribo-seq]

ABSTRACT: Naa10 is a Nα-terminal acetyltransferase that, in a complex with its auxiliary subunit Naa15, co-translationally acetylates the α-amino group of newly synthetized proteins as they emerge from the ribosome. Roughly 40-50% of the human proteome is acetylated by Naa10, rendering this an enzyme with one of the most broad substrate ranges known. Recently, we reported an X-linked disorder of infancy, Ogden syndrome, in two families harboring a c.109T>C (p.Ser37Pro) variant in NAA10. In the present study we performed in-depth characterization of a yeast model of Ogden syndrome. Stress tests and proteomic analyses suggest that the S37P mutation disrupts Naa10 function and reduces cellular fitness during heat shock, possibly due to dysregulation of chaperone expression and accumulation. Microarray and RNA-seq revealed a pseudo-diploid gene expression profile in ΔNaa10 cells, likely responsible for a mating defect. In conclusion, the data presented here further support the disruptive nature of the S37P/Ogden mutation and identify affected cellular processes potentially contributing to the severe phenotype seen in Ogden syndrome.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE86466 | GEO | 2016/09/07

SECONDARY ACCESSION(S): PRJNA342004

REPOSITORIES: GEO

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Proteomic and genomic characterization of a yeast model for Ogden syndrome [microarray]

Project description:Gene expression microarrays accompanying "Proteomic and genomic characterization of a yeast model for Ogden syndrome" by Doerfel et al 2016 in press at Yeast. Naa10 is a Na-terminal acetyltransferase that, in a complex with its auxiliary subunit Naa15, co-translationally acetylates the a-amino group of newly synthetized proteins as they emerge from the ribosome. Roughly 40-50% of the human proteome is acetylated by Naa10, rendering this an enzyme with one of the most broad substrate ranges known. Recently, we reported an X-linked disorder of infancy, Ogden syndrome, in two families harboring a c.109T>C (p.Ser37Pro) variant in NAA10. In the present study we performed in-depth characterization of a yeast model of Ogden syndrome. Stress tests and proteomic analyses suggest that the S37P mutation disrupts Naa10 function and reduces cellular fitness during heat shock, possibly due to dysregulation of chaperone expression and accumulation. Microarray and RNA-seq revealed a pseudo-diploid gene expression profile in DNaa10 cells, likely responsible for a mating defect. In conclusion, the data presented here further support the disruptive nature of the S37P/Ogden mutation and identify affected cellular processes potentially contributing to the severe phenotype seen in Ogden syndrome.

2016-09-03 | GSE86358 | GEO

Proteomic and genomic characterization of a yeast model for Ogden Syndrome

Project description:Naa10 is a N-terminal acetyltransferase that, in a complex with its auxiliary subunit Naa15, co-translationally acetylates the -amino group of newly synthetized proteins as they emerge from the ribosome. Roughly 40-50% of the human proteome is acetylated by Naa10, rendering this an enzyme with one of the most broad substrate ranges known. Recently, we reported an X-linked disorder of infancy, Ogden syndrome, in two families harboring a c.109T>C (p.Ser37Pro) variant in NAA10. In the present study we performed in-depth characterization of a yeast model of Ogden syndrome. Stress tests and proteomic analyses suggest that the S37P mutation disrupts Naa10 function and reduces cellular fitness during heat shock, possibly due to dysregulation of chaperone expression and accumulation. Microarray and RNA-seq revealed a pseudo-diploid gene expression profile in Naa10 cells, likely responsible for a mating defect. In conclusion, the data presented here further support the disruptive nature of the S37P/Ogden mutation and identify affected cellular processes potentially contributing to the severe phenotype seen in Ogden syndrome.

2016-09-28 | PXD004923 | Pride

Differential N-terminal COFRADIc analyses of Ogden fibroblasts

Project description:The X-linked lethal Ogden syndrome was the first reported human genetic disorder associated with a mutation in an N-terminal acetyltransferase gene. The affected males harbour a Ser37Pro mutation in the gene encoding hNaa10, the catalytic subunit of NatA, themajor human NAT. In order to understand the detrimental impact of hNaa10 Ser37Pro, we performed structural, molecular and cellular investigations. Structural models and molecular dynamics simulations of the human NatA and its Ser37Pro mutant suggest differences in regions involved in catalysis and at the interface between hNaa10 and the auxiliary subunit hNaa15. In agreement, biochemical data demonstrate a reduced catalytic capacity and an impaired NatA complex formation with hNaa10 Ser37Pro. Patient derived Naa10 mutant cells show reduced Nt-acetylation for a subset of NatA/NatE-type substrates compared to wild type Naa10 cells. Ogden syndrome fibroblasts further display abnormal cell proliferation and migration capacity, possibly linked to perturbed Retinoblastoma- and MYLK-pathways, respectively. Differential N-terminal combined fractional diagonal chromatography (COFRADIC) was used to quantify the degree and define the patterns of in vivo protein Nt-acetylation and here used to investigate whether patient cells derived from an affected Ogden male (carrying the Naa10 S37P mutation) displayed altered levels of protein Nt-acetylation at the proteome-wide level.

2016-04-12 | PXD001282 | Pride

Mass-spectrometry based quantification of HYPK, NAA10 and NAA15 protein steady-state levels in Arabidopsis thaliana mutants carrying a T-DNA insertion in the HYPK gene.

Project description:N-alpha terminal acetylation is one of the major protein modifications in eukaryotes carried out by distinct Nats (N-alpha acetyltransferases). The core NatA complex is composed of the catalytic NAA10 and the auxiliary NAA15 subunit and co-translationally acetylates majority of the cytosolic proteins. HYPK interacts with NatA core complex in human and fungus in vivo and in vitro, regulating its activity. Here, a mass spectrometry approach was applied to quantify the steady-state levels of the core NatA subunits, NAA10 and NAA15 and of HYPK in the roots of Arabidopsis mutants carrying a T-DNA insertion in the HYPK gene (AT3G06610).

2022-08-12 | PXD023599 | Pride

LC-MS/MS analysis of immunoprecipitated NAA15-V5 variants

Project description:The human N-terminal acetyltransferase E (NatE) including its associated NatA co-translationally acetylates the N-terminus of about 40-60% of the proteome to mediate diverse biological processes including protein half-life, localization and protein interaction. In eukaryotes, the NatE complex contains the NAA50 catalytic subunit with substrate specificity for N-terminal methionine acetylation and NatA, which facilitates ribosomal targeting of the complex for co-translational activity. NatA, contains NAA10 catalytic and NAA15 auxiliary subunits, and forms a complex with a protein with intrinsic NAA10 inhibitory activity, HYPK. The molecular basis for how the human NAA10 and NAA50 catalytic subunits within NatE complex coordinate function and how HYPK regulates NatE activity is unknown. Here, we characterize the biochemical interplay between the human NAA10 and NAA50 catalytic subunits of NatE and its regulation by HYPK and correlate this to the cryo-EM structures of the human NatE and NatE/HYPK complexes. We show that NAA50 and HYPK exhibit negative cooperative binding to NatA in vitro and in human cells, by inducing NAA15 shifts in opposing directions. NAA50 and HYPK each contributes to NAA10 activity inhibition through structural alteration of the NAA10 substrate binding site. NatE is about 8-fold more active than NAA50, likely due to a reduced entropic cost for substrate binding through NatA tethering, but is inhibited by HYPK through structural alteration of the NatE substrate binding site. Taken together, these studies reveal the molecular basis for coordinated N-terminal acetylation by the NAA10 and NAA50 catalytic subunits of NatE and its modulation by HYPK.

2020-03-13 | PXD017031 | Pride

Identification of drought stress related genes in NatA depleted mutants

Project description:N-terminal protein acetylation is one of the most common protein modifications in eucaryotes and is catalyzed co-translationally by N-terminal aceytltransferases (Nats). Regarding the number of predictaed substrates, NatA is the main Nat complex in human and yeast and is composed of the catalytic subunit NAA10 and the auxilliary subunit NAA15. The down-regulation of NAA10 and NAA15 results in Arabidopsis in drought resistant plants. This study focus on the identification of altered gene expression leading to the drought resistant phenotype. Microarray analysis was used to identify misregulated genes in the NatA depleted mutants responsible for the drought resistant phenotype Arabidopsis thaliana plants were grown on soil for 6 weeks under short-day conditions (8h light / 16h dark cycles) with normal watering and subsequently challenged with drought for 10 days. After 10 days of drought Arabidopsis leaf material was harvested and used for RNA extraction and hybridization on Affymetrix microarrays. Four biological replicates from each genotype and condition were analyzed.

2015-07-23 | E-GEOD-65414 | biostudies-arrayexpress

Identification of drought stress related genes in NatA depleted mutants

2015-07-23 | GSE65414 | GEO

Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

Project description:Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR). How allele-specific DNA methylation at ICR is regulated is largely unknown. Mammalian N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins. Mutation of human Naa10p is linked to severe developmental defects and mental retardation, including the Ogden syndrome. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorder and maternal-effect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses reveal global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-null embryos and ES cells. Naa10p regulates global DNA methylation by stimulating DNA methyltransferase 1 (Dnmt1) activity, while maintaining imprinted allele methylation by binding to GCXGXG and recruits Dnmt1. Clinical mutation of Naa10p disrupts its H19-ICR binding and Dnmt1 recruitment. Our study thus links Naa10p mutation-associated human diseases to defective DNA methylation and genomic imprinting.

2017-09-29 | GSE83206 | GEO

Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting

Project description:Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), of which the underlying mechanism remains largely unclear. Mammalian N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins. Mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorder and maternaleffect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and ES cells. Mechanistically, Naa10p facilitates the binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates and recruits Dnmt1 to ICRs of the imprinted allele during S phase. Moreover, the clinical lethal Ogden syndrome-associated mutation of Naa10p disrupts its binding to H19-ICR and Dnmt1 recruitment. Our study thus links Naa10p mutationassociated human disease to defective DNA methylation and genomic imprinting.

2017-10-05 | GSE102224 | GEO

Expression data from Arabidopsis thaliana depleted of HYPK or NAA10

Project description:N-alpha terminal acetylation is an abundant protein modification in eukaryotes. The NatA (N-alpha acetyltransferase A) complex is responsible for N-terminal acetylation of majority of the cytosolic proteins and its core is composed of NAA10 and NAA15 subunit. HYPK has been shown to interact with NatA core complex in human and fungus, modulating its activity. Here we address the in vivo function of the plant HYPK protein. A transcriptomics approach was applied to compare transcriptional reprogramming induced by depletion of NAA10 or HYPK mutants in plants.

2022-05-20 | GSE158586 | GEO

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