Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Aksnes, Henriette; Ree, Rasmus; Arnesen, Thomas

doi:10.1016/j.molcel.2019.02.007

Cited by 180 publications

(275 citation statements)

References 146 publications

(206 reference statements)

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“…NatB mediated Ntacetylation is efficient, and nearly all proteins that code as NatB substrates are indeed NatB substrates, which is not true for other Nt-acetyltransferases. Interestingly, yeast NatB substrates are predominantly, near 100%, found in the acetylated state [28,29]. In line with these observations, we showed that Nma1 and Nma2 peptides identified from WT cells were 100% acetylated whereas Nma1 or Nma2 peptides identified from NatB mutants were 95%-100% non-acetylated [21].…”

Section: Introductionsupporting

confidence: 84%

“…NatA substrates are not Met-retained like NatB substrates, but first undergo a processing by removal of the initiator methionine by methionine aminopeptidases, and the new aminoterminus is then acetylated by NatA ( Fig. 2A, left panel) [28]. Additionally, potential…”

Section: Natb Promotes Nad + Biosynthesis Directly Through Nt-acetylamentioning

confidence: 99%

“…Based on reported proteomic data we chose to insert Ser between the first two amino acids, Met and Asp, in Nma1 and Nma2 (Nma1/2 MD à Nma1/2 MSD ) ( Fig. 2A, right panel) because this peptide sequence is almost always acetylated by NatA [28,29].…”

Section: Natb Promotes Nad + Biosynthesis Directly Through Nt-acetylamentioning

confidence: 99%

“…The levels of Nma1 and Nma2 proteins were reduced in NatB deletion mutants compared to wild type (WT). Ntacetylation is primarily a co-translational protein modification and carried out by a Ntacetyltransferases [28]. Nt-acetylation neutralizes the positive charge carried by the free amino group making the N-terminus more hydrophobic.…”

Section: Introductionmentioning

confidence: 99%

“…Nt-acetylation neutralizes the positive charge carried by the free amino group making the N-terminus more hydrophobic. This protein modification has potential to alter folding, complex formation, localization, and degradation [28]. NatB carries out Nt-acetylation of approximately 15% of encoded yeast proteins, which are Met-retained peptides with Asp, Asn, Glu or Gln at position two.…”

Section: Introductionmentioning

confidence: 99%

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N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Croft

Venkatakrishnan

Raj

et al. 2019

Preprint

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ABSTRACTNAD+ is an essential metabolite participating in cellular biochemical processes and signaling. The regulation and interconnection among multiple NAD+ biosynthesis pathways are not completely understood. We previously identified the N-terminal (Nt) protein acetyltransferase complex NatB as a NAD+ homeostasis factor. Cells lacking NatB show an approximate 50% reduction in the NAD+ level and aberrant metabolism of NAD+ precursors, which are associated with a decrease of nicotinamide mononucleotide adenylyltransferases (Nmnat) protein levels. Here we show this decrease in NAD+ and Nmnat protein levels is specifically due to the absence of Nt-acetylation of Nmnat (Nma1 and Nma2) proteins, and not other NatB substrates. Nt-acetylation is a critical regulator of protein degradation by the N-end rule pathways, indicating absence of Nt-acetylation may alter Nmnat protein stability. Interestingly, the rate of protein turnover (t1/2) of non-Nt-acetylated Nmnats does not significantly differ from Nt-acetylated Nmnats, suggesting reduced Nmnat levels in NmatB mutants are not due to increased post-translational degradation of non-Nt-acetylated Nmnats. In line with these observations, deletion or depletion of N-rule pathway ubiquitin E3 ligases in NatB mutants is not sufficient to restore NAD+ levels. Moreover, the status of Nt-acetylation does not alter the rate of translation initiation of Nmnats. Collectively our studies suggest absence of Nt-acetylation may increase co-translational degradation of nascent Nmnat polypeptides, which results in reduced Nmnat levels in NatB mutants. Nmnat activities are essential for all routes of NAD+ biosynthesis. Understanding the regulation of Nmnat protein homeostasis will facilitate our understanding of the molecular basis and regulation of NAD+ metabolism.

show abstract

Section: Introductionsupporting

confidence: 84%

Section: Natb Promotes Nad + Biosynthesis Directly Through Nt-acetylamentioning

confidence: 99%

Section: Natb Promotes Nad + Biosynthesis Directly Through Nt-acetylamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Croft

Venkatakrishnan

Raj

et al. 2019

Preprint

View full text Add to dashboard Cite

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Acetylation stabilises calmodulin‐regulated calcium signalling

2022

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Calmodulin is a conserved calcium signalling protein that regulates a wide range of cellular functions. Amino-terminal acetylation is a ubiquitous posttranslational modification that affects the majority of human proteins, to stabilise structure, as well as regulate function and proteolytic degradation.Here, we present data on the impact of amino-terminal acetylation upon structure and calcium signalling function of fission yeast calmodulin. We show that NatA-dependent acetylation stabilises the helical structure of the Schizosaccharomyces pombe calmodulin, impacting its ability to associate with myosin at endocytic foci. We go on to show that this conserved modification impacts both the calcium-binding capacity of yeast and human calmodulins. These findings have significant implications for research undertaken into this highly conserved essential protein.

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A nonsense variant in the N‐terminal acetyltransferase NAA30 may be associated with global developmental delay and tracheal cleft

Varland

Brønstad

Skinner

et al. 2023

American J of Med Genetics Pt A

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Most human proteins are N‐terminally acetylated by N‐terminal acetyltransferases (NATs), which play crucial roles in many cellular functions. The NatC complex, comprising the catalytic subunit NAA30 and the auxiliary subunits NAA35 and NAA38, is estimated to acetylate up to 20% of the human proteome in a co‐translational manner. Several NAT enzymes have been linked to rare genetic diseases, causing developmental delay, intellectual disability, and heart disease. Here, we report a de novo heterozygous NAA30 nonsense variant c.244C>T (p.Q82*) (NM_001011713.2), which was identified by whole exome sequencing in a 5‐year‐old boy presenting with global development delay, autism spectrum disorder, hypotonia, tracheal cleft, and recurrent respiratory infections. Biochemical studies were performed to assess the functional impact of the premature stop codon on NAA30's catalytic activity. We find that NAA30‐Q82* completely disrupts the N‐terminal acetyltransferase activity toward a classical NatC substrate using an in vitro acetylation assay. This finding corresponds with structural modeling showing that the truncated NAA30 variant lacks the entire GNAT domain, which is required for catalytic activity. This study suggests that defective NatC‐mediated N‐terminal acetylation can cause disease, thus expanding the spectrum of NAT variants linked to genetic disease.

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Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Cited by 180 publications

References 146 publications

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

Acetylation stabilises calmodulin‐regulated calcium signalling

A nonsense variant in the N‐terminal acetyltransferase NAA30 may be associated with global developmental delay and tracheal cleft

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Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Cited by 180 publications

References 146 publications

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD+biosynthetic enzymes inSaccharomyces cerevisiae

Acetylation stabilises calmodulin‐regulated calcium signalling

A nonsense variant in the N‐terminal acetyltransferase NAA30 may be associated with global developmental delay and tracheal cleft

Contact Info

Product

Resources

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N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae

N-terminal protein acetylation by NatB modulates the levels of Nmnats, the NAD⁺biosynthetic enzymes inSaccharomyces cerevisiae