Synthetic lethal screen of NAA20, a catalytic subunit gene of NatB N-terminal acetylase in Saccharomyces cerevisiae

Lee, Kang-Eun; Ahn, Jungkyu; Kim, Jeong-Mok; Hwang, Cheol-Sang

doi:10.1007/s12275-014-3694-z

Cited by 6 publications

(4 citation statements)

References 38 publications

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“…However, hNAA20 and hNAA25 share only ~40% and~20% sequence identity with the Candida albicans homolog ( Hong et al, 2017 ), respectively. Moreover, nearly all biological studies of NatB have been conducted in Saccharomyces cerevisiae ( Lee et al, 2014 ; Caesar et al, 2006 ; Singer and Shaw, 2003 ), Arabidopsis ( Ferrández-Ayela et al, 2013 ; Huber et al, 2020 ), mouse ( Ohyama et al, 2012 ), and human ( Starheim et al, 2008 ; Ametzazurra et al, 2008 ; Ametzazurra et al, 2009 ; Neri et al, 2017 ) as model organisms. As a result, the mode of human NatB-mediated catalysis and αSyn-specific NatB recognition remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

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Molecular basis for N-terminal alpha-synuclein acetylation by human NatB

Deng

Pan

Gottlieb

et al. 2020

eLife

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NatB is one of three major N-terminal acetyltransferase (NAT) complexes (NatA-NatC), which co-translationally acetylate the N-termini of eukaryotic proteins. Its substrates account for about 21% of the human proteome, including well known proteins such as actin, tropomyosin, CDK2, and α-synuclein (aSyn). Human NatB (hNatB) mediated N-terminal acetylation of αSyn has been demonstrated to play key roles in Parkinson's disease pathogenesis and as a potential therapeutic target for hepatocellular carcinoma. Here we report the cryo-EM structure of hNatB bound to a CoA-aSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis reveals functionally important differences with human NatA and Candida albicans NatB, resolves key hNatB protein determinants for aSyn N-terminal acetylation, and identifies important residues for substrate-specific recognition and acetylation by NatB enzymes. These studies have implications for developing small molecule NatB probes and for understanding the mode of substrate selection by NAT enzymes.

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Section: Introductionmentioning

confidence: 99%

“…However, hNAA20 and hNAA25 share only ~40% and ~20% sequence identity with the Candida albicans homologue [58], respectively. Moreover, nearly all biological studies of NatB have been conducted in Saccharomyces cerevisiae [59][60][61],…”

Section: Introductionmentioning

confidence: 99%

Molecular basis for N-terminal alpha-synuclein acetylation by human NatB

Deng

Pan

Gottlieb

et al. 2020

eLife

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show abstract

“…However, hNAA20 and hNAA25 share only ~40% and ~20% sequence identity with the Candida albicans homologue [57], respectively. Moreover, nearly all biological studies of NatB have been conducted in Saccharomyces cerevisiae [58][59][60], Arabidopsis [61,62], mouse [63] and human [17,[43][44][45] as model organisms. As a result, the mode of human NatB-mediated catalysis and aSyn-specific NatB recognition remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis for N-terminal Alpha-Synuclein Acetylation by Human NatB

Marmorstein

Deng

Pan

et al. 2020

Preprint

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NatB is one of three major N-terminal acetyltransferase (NAT) complexes (NatA-NatC), which co-translationally acetylate the N-termini of eukaryotic proteins. Its substrates account for about 21% of the human proteome, including well known proteins such as actin, tropomyosin, CDK2, and αsynuclein (aSyn). Human NatB (hNatB) mediated N-terminal acetylation of αSyn has been demonstrated to play key roles in Parkinson's disease pathogenesis and as a potential therapeutic target for hepatocellular carcinoma.Here we report the cryo-EM structure of hNatB bound to a CoA-aSyn conjugate, together with structure-guided analysis of mutational effects on catalysis. This analysis reveals functionally important differences with human NatA and Candida albicans NatB, resolves key hNatB protein determinants for aSyn Nterminal acetylation, and identifies important residues for substrate-specific recognition and acetylation by NatB enzymes. These studies have implications for developing small molecule NatB probes and for understanding the mode of substrate selection by NAT enzymes.

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“…NatB plays roles in cell growth in response to various stressors, mitochondrial inheritance, actin cable formation, cell wall maintenance, flowering regulation, plant development, etc. ( Aksnes et al, 2015b ; Ferrandez-Ayela et al, 2013 ; Lee et al, 2014 ).…”

Section: Nt-acetylation Machinery and Functionsmentioning

confidence: 99%

N-Terminal Acetylation-Targeted N-End Rule Proteolytic System: The Ac/N-End Rule Pathway

Lee

Heo

Kim

et al. 2016

Molecules and Cells

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Although Nα-terminal acetylation (Nt-acetylation) is a pervasive protein modification in eukaryotes, its general functions in a majority of proteins are poorly understood. In 2010, it was discovered that Nt-acetylation creates a specific protein degradation signal that is targeted by a new class of the N-end rule proteolytic system, called the Ac/N-end rule pathway. Here, we review recent advances in our understanding of the mechanism and biological functions of the Ac/N-end rule pathway, and its crosstalk with the Arg/N-end rule pathway (the classical N-end rule pathway).

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Synthetic lethal screen of NAA20, a catalytic subunit gene of NatB N-terminal acetylase in Saccharomyces cerevisiae

Cited by 6 publications

References 38 publications

Molecular basis for N-terminal alpha-synuclein acetylation by human NatB

Molecular basis for N-terminal alpha-synuclein acetylation by human NatB

Molecular Basis for N-terminal Alpha-Synuclein Acetylation by Human NatB

N-Terminal Acetylation-Targeted N-End Rule Proteolytic System: The Ac/N-End Rule Pathway

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