The Human N-Alpha-Acetyltransferase 40 (hNaa40p/hNatD) Is Conserved from Yeast and N-Terminally Acetylates Histones H2A and H4

Hole, Kristine; Damme, Petra Van; Dalva, Monica; Aksnes, Henriette; Glomnes, Nina; Varhaug, Jan Erik; Lillehaug, Johan R.; Gevaert, Kris; Arnesen, Thomas

doi:10.1371/journal.pone.0024713

Cited by 106 publications

(133 citation statements)

References 48 publications

(63 reference statements)

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…When looking into their sequence profile it is of note that they predominantly display the NatD type substrate specificity (6). Of note, the SGGKG-starting N terminus of H2A was fully Nt-acetylated in all four setups analyzed in agreement with it being a NatD substrate (56).…”

Section: Discussionmentioning

confidence: 70%

See 1 more Smart Citation

A Saccharomyces cerevisiae Model Reveals In Vivo Functional Impairment of the Ogden Syndrome N-Terminal Acetyltransferase NAA10 Ser37Pro Mutant

Damme

Støve

Glomnes

et al. 2014

Molecular & Cellular Proteomics

Self Cite

View full text Add to dashboard Cite

N-terminal acetylation (Nt-acetylation) occurs on the majority of eukaryotic proteins and is catalyzed by N-terminal acetyltransferases (NATs). Nt-acetylation is increasingly recognized as a vital modification with functional implications ranging from protein degradation to protein localization. Although early genetic studies in yeast demonstrated that NAT-deletion strains displayed a variety of phenotypes, only recently, the first human genetic disorder caused by a mutation in a NAT gene was reported; boys diagnosed with the X-linked Ogden syndrome harbor a p.Ser37Pro (S37P) mutation in the gene encoding Naa10, the catalytic subunit of the NatA complex, and suffer from global developmental delays and lethality during infancy. Here, we describe a Saccharomyces cerevisiae model developed by introducing the human wild-type or mutant NatA complex into yeast lacking NatA (NatA-⌬). The wild-type human NatA complex phenotypically complemented the NatA-⌬ strain, whereas only a partial rescue was observed for the Ogden mutant NatA complex suggesting that hNaa10 S37P is only partially functional in vivo. Immunoprecipitation experiments revealed a reduced subunit complexation for the mutant hNatA S37P next to a reduced in vitro catalytic activity. We performed quantitative Nt-acetylome analyses on a control yeast strain (yNatA), a yeast NatA deletion strain (yNatA-⌬), a yeast NatA deletion strain expressing wild-type human NatA (hNatA), and a yeast NatA deletion strain expressing mutant human NatA (hNatA S37P). Interestingly, a generally reduced degree of Nt-acetylation was observed among a large group of NatA substrates in the yeast expressing mutant hNatA as compared with yeast expressing wild-type hNatA. Combined, these data provide strong support for the functional impairment of hNaa10 S37P in vivo and suggest that reduced Nt-acetylation of one or more target substrates contributes to the pathogenesis of the Ogden syndrome. Comparative analysis between human and yeast NatA also provided new insights into the co-evolution of the NatA complexes and their substrates. For instance, (Met-)Ala-

show abstract

Section: Discussionmentioning

confidence: 70%

“…In addition, a putative hNatE complex has been described (9 -10). Except for NatF, which is only expressed in higher eukaryotes (1), the substrate specificity profiles of the NatA-E complexes seem to be conserved among eukaryotes (5)(6)(7)(8)(9)(11)(12)(13).…”

mentioning

confidence: 99%

A Saccharomyces cerevisiae Model Reveals In Vivo Functional Impairment of the Ogden Syndrome N-Terminal Acetyltransferase NAA10 Ser37Pro Mutant

Damme

Støve

Glomnes

et al. 2014

Molecular & Cellular Proteomics

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, most of these studies used limited number of synthetic peptides that mimic the natural substrates, whereas some others used the whole cell proteome to understand the substrate specificity (5,13,24). Based on these studies, it was established that different NAT complexes have preferences for different amino termini.…”

Section: Resultsmentioning

confidence: 99%

“…For example, NatA, which is a complex of Naa10 and Naa15, has been implicated in acetylating peptides that have small and uncharged amino acids at the amino terminus that are formed after the removal of initiator methionine by MetAP (8). Similarly, Naa50 acetylates the amino-terminal methionine that is followed by leucine, isoleucine, phenylalanine, and tryptophan (8,13). Because our x-ray crystal structure suggests Met-Met in the first two positions, we designed a series of tetrapeptides to explore the substrate specificity of Naa50.…”

Section: Resultsmentioning

confidence: 99%

“…NatA acetylates the peptides with serine, alanine, threonine, cysteine, and valine on the amino termini that are formed after MetAP action at the ribosome exit tunnel (5,9), whereas NatB acts on methionine followed by acidic residues in the second position (10,11). NatC, NatE, and NatF act on methionine that is followed by hydrophobic amino acids like leucine, phenylalanine, isoleucine, and tryptophan (8,10,12,13). Additionally, NatF also acetylates methionine that is followed specifically by a lysine (14).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Human Naa50 Protein Displays Broad Substrate Specificity for Amino-terminal Acetylation

Reddi¹,

Saddanapu²,

Chinthapalli

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Amino-terminal acetylation is a critical co-translational modification of the newly synthesized proteins in a eukaryotic cell carried out by six amino-terminal acetyltransferases (NATs). All NATs contain at least one catalytic subunit, and some contain one or two additional auxiliary subunits. For example, NatE is a complex of Naa10, Naa50, and Naa15 (auxiliary). In the present study, the crystal structure of human Naa50 suggested the presence of CoA and acetylated tetrapeptide (AcMMXX) that have co-purified with the protein. Biochemical and thermal stability studies on the tetrapeptide library with variations in the first and second positions confirm our results from the crystal structure that a peptide with Met-Met in the first two positions is the best substrate for this enzyme. In addition, Naa50 acetylated all MXAA peptides except for MPAA. Transcriptome analysis of 10 genes that make up six NATs in humans from eight different cell lines suggests that components of NatE are transcribed in all cell lines, whereas others are variable. Because Naa10 is reported to acetylate all amino termini that are devoid of methionine and Naa50 acetylates all other peptides that are followed by methionine, we believe that NatE complex can be a major contributor for amino-terminal acetylation at the ribosome exit tunnel.Co-translational protein modifications are important biochemical events. Prominent among them are amino-terminal modifications such as methionine cleavage, acetylation, and myristoylation (1-3). Initiator methionine in eukaryotic proteins is removed co-translationally by the enzyme methionine aminopeptidase (MetAP) 3 when the second amino acid is small and uncharged (1). About 70% of the matured proteins do not retain their amino-terminal methionine (4). Similarly, about 90% of all newly synthesized cytosolic proteins undergo aminoterminal acetylation (5). Protein amino-terminal acetylation is carried out by six amino-terminal acetyltransferases (NATs) named sequentially NatA to NatF, classified based on substrate preference (6 -8). NatA acetylates the peptides with serine, alanine, threonine, cysteine, and valine on the amino termini that are formed after MetAP action at the ribosome exit tunnel (5, 9), whereas NatB acts on methionine followed by acidic residues in the second position (10, 11). NatC, NatE, and NatF act on methionine that is followed by hydrophobic amino acids like leucine, phenylalanine, isoleucine, and tryptophan (8, 10, 12, 13). Additionally, NatF also acetylates methionine that is followed specifically by a lysine (14). NatD acetylates the amino termini of Ser-Gly of histones H2A and H4 (15). Each of the NATs (NatA-NatF) is a complex of one or two of the enzymes labeled serially as Naa10, Naa20, Naa30, Naa40, Naa50, and Naa60 attached to one or two of the auxiliary proteins named Naa15, Naa25, Naa35, and Naa38 (7, 9). Some NATs are known to bind to the ribosome at the exit tunnel through their auxiliary subunits (11, 16). Protein amino-terminal acetylation has potential effects on cell ...

show abstract

Does N‐Terminal Protein Acetylation Lead to Protein Degradation?

et al. 2019

View full text Add to dashboard Cite

The N-end rule denotes the relationship between the identity of the amino-terminal residue of a protein and its in vivo half-life. Since its discovery in 1986, the N-end rule has generally been described by a defined set of rules for determining whether an amino-terminal residue is stabilizing or not. However, recent studies are revealing that this N-end rule (or N-degron concept) is less straightforward than previously appreciated. For instance, it is unveiled that N-terminal acetylation of N-terminal residues may create a degradation signal (Ac-degron) that promotes the degradation of target proteins. A recent high-throughput dissection of degrons in yeast proteins amino termini intriguingly suggested that the hydrophobicity of amino-terminal residues-but not the N-terminal acetylation status-may be the indispensable feature of amino-terminal degrons. Herein, these recent advances in N-terminal acetylation and the complexity of N-terminal degradation signals in the context of the N-degron pathway are analyzed.

show abstract

The Human N-Alpha-Acetyltransferase 40 (hNaa40p/hNatD) Is Conserved from Yeast and N-Terminally Acetylates Histones H2A and H4

Cited by 106 publications

References 48 publications

A Saccharomyces cerevisiae Model Reveals In Vivo Functional Impairment of the Ogden Syndrome N-Terminal Acetyltransferase NAA10 Ser37Pro Mutant

A Saccharomyces cerevisiae Model Reveals In Vivo Functional Impairment of the Ogden Syndrome N-Terminal Acetyltransferase NAA10 Ser37Pro Mutant

Human Naa50 Protein Displays Broad Substrate Specificity for Amino-terminal Acetylation

Does N‐Terminal Protein Acetylation Lead to Protein Degradation?

Contact Info

Product

Resources

About