Metabolic Regulation of Protein N-Alpha-Acetylation by Bcl-xL Promotes Cell Survival

Yi, Caroline H.; Pan, Heling; Seebacher, Jan; Jang, Il Ho; Hyberts, Sven G.; Heffron, Gregory J.; Heiden, Matthew G. Vander; Yang, Renliang; Li, Fupeng; Locasale, Jason W.; Sharfi, Hadar; Zhai, Bo; Rodriguez‐Mias, Ricard A.; Luithardt, Harry; Cantley, Lewis C.; Daley, George Q.; Asara, John M.; Gygi, Steven P.; Wagner, Gerhard; Liu, Chuan‐Fa; Yuan, Junying

doi:10.1016/j.cell.2011.06.050

Cited by 191 publications

(183 citation statements)

References 43 publications

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“…Thus, proteins devoid of NAA signal would be preferentially guided to the secretory pathway in yeast. Next, it is now suggested that NAA is not only controlled by the level of the enzymes involved but mainly by the level of its substrate, namely acetyl-CoA (40). Such metabolic regulation would be crucial to promote, for instance, apoptosis in mammals.…”

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confidence: 99%

Comparative Large Scale Characterization of Plant versus Mammal Proteins Reveals Similar and Idiosyncratic N-α-Acetylation Features

Bienvenut

Sumpton

Martinez

et al. 2012

Molecular & Cellular Proteomics

159

193

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confidence: 99%

Comparative Large Scale Characterization of Plant versus Mammal Proteins Reveals Similar and Idiosyncratic N-α-Acetylation Features

Bienvenut

Sumpton

Martinez

et al. 2012

Molecular & Cellular Proteomics

159

193

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“…structural biology | evolutionary biology | enzymology | X-ray crystallography T he cotranslational process of amino-terminal acetylation occurs on a majority of eukaryotic proteins and mediates many biological processes, including cellular apoptosis, enzymatic regulation, protein localization, and protein degradation (1)(2)(3)(4). In humans, three major amino-terminal acetyltransferase (NAT) complexes, called NatA, NatB, and NatC, are responsible for modifying ∼85% of all proteins that undergo amino-terminal acetylation (5).…”

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confidence: 99%

Implications for the evolution of eukaryotic amino-terminal acetyltransferase (NAT) enzymes from the structure of an archaeal ortholog

Liszczak

Marmorstein

2013

Proc. Natl. Acad. Sci. U.S.A.

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Amino-terminal acetylation is a ubiquitous modification in eukaryotes that is involved in a growing number of biological processes. There are six known eukaryotic amino-terminal acetyltransferases (NATs), which are differentiated from one another on the basis of substrate specificity. To date, two eukaryotic NATs, NatA and NatE, have been structurally characterized, of which NatA will acetylate the α-amino group of a number of nonmethionine amino-terminal residue substrates such as serine; NatE requires a substrate amino-terminal methionine residue for activity. Interestingly, these two NATs use different catalytic strategies to accomplish substrate-specific acetylation. In archaea, where this modification is less prevalent, only one NAT enzyme has been identified. Surprisingly, this enzyme is able to acetylate NatA and NatE substrates and is believed to represent an ancestral NAT variant from which the eukaryotic NAT machinery evolved. To gain insight into the evolution of NAT enzymes, we determined the X-ray crystal structure of an archaeal NAT from Sulfolobus solfataricus (ssNAT). Through the use of mutagenesis and kinetic analysis, we show that the active site of ssNAT represents a hybrid of the NatA and NatE active sites, and we highlight features of this protein that allow it to facilitate catalysis of distinct substrates through different catalytic strategies, which is a unique characteristic of this enzyme. Taken together, the structural and biochemical data presented here have implications for the evolution of eukaryotic NAT enzymes and the substrate specificities therein.structural biology | evolutionary biology | enzymology | X-ray crystallography T he cotranslational process of amino-terminal acetylation occurs on a majority of eukaryotic proteins and mediates many biological processes, including cellular apoptosis, enzymatic regulation, protein localization, and protein degradation (1-4). In humans, three major amino-terminal acetyltransferase (NAT) complexes, called NatA, NatB, and NatC, are responsible for modifying ∼85% of all proteins that undergo amino-terminal acetylation (5). These complexes are conserved in yeast, exist as obligate heterodimers, and are differentiated from one another on the basis of substrate specificity, which is dictated by the amino-terminal sequence of the substrate protein (5, 6). Each complex consists of a single unique catalytic subunit and an additional unique auxiliary subunit that has been shown to potentiate activity and alter substrate specificity of the enzymatic component, as well as anchor the complex to the ribosome during translation (6-11). Three additional human NAT enzymes, NatD-NatF, have also been identified, but they have a much more limited set of physiological substrates, appear to be independently active, and are not well characterized across eukaryotes (12)(13)(14).The only two eukaryotic NATs that have been structurally characterized are Schizosaccharomyces pombe NatA, consisting of the Naa10p catalytic subunit and Naa15p regulatory subunit, and ...

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“…ATP also serves as an extracellular signaling molecule involved in vascular tone, synaptic transmission, and cell death (6,7). Cellular ATP levels have been reported to reflect cell viability, including cell survival, cell growth, and morphology (8,9). Furthermore, it has been reported that complete ATP depletion (Ͻ5% of control) results in necrosis, and partial ATP depletion (ϳ10 -65% of control) induces apoptosis, as evidenced by internucleosomal DNA cleavage, changes in cellular morphology, and alterations in the plasma membrane (10).…”

mentioning

confidence: 99%

Intracellular and Extracellular ATP Coordinately Regulate the Inverse Correlation between Osteoclast Survival and Bone Resorption

Miyazaki

Iwasawa

Nakashima

et al. 2012

Journal of Biological Chemistry

110

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Background: Mature osteoclasts with a spontaneous tendency toward apoptosis resorb bone efficiently during their short lifespan. Results: Released ATP from intracellular stores has a negative impact on the bone resorption activity of osteoclasts by altering their cytoskeletal structures. Conclusion: ATP depletion leads to osteoclastic bone resorption. Significance: This study provides a new direction for investigating the mechanisms involved in physiological and pathological bone resorption.

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Metabolic Regulation of Protein N-Alpha-Acetylation by Bcl-xL Promotes Cell Survival

Cited by 191 publications

References 43 publications

Comparative Large Scale Characterization of Plant versus Mammal Proteins Reveals Similar and Idiosyncratic N-α-Acetylation Features

Comparative Large Scale Characterization of Plant versus Mammal Proteins Reveals Similar and Idiosyncratic N-α-Acetylation Features

Implications for the evolution of eukaryotic amino-terminal acetyltransferase (NAT) enzymes from the structure of an archaeal ortholog

Intracellular and Extracellular ATP Coordinately Regulate the Inverse Correlation between Osteoclast Survival and Bone Resorption

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