NAA40 (N-alpha-acetyltransferase 40; also NatD/Nat4/Nat11) is a highly substrate-specific N-terminal acetyltransferase that acetylates the free alpha-amino group of the N-terminal serine of histones H4 and H2A (which share an identical Ser-Gly-Arg-Gly N-terminal sequence after initiator-methionine removal), producing N-terminally acetylated H4/H2A (EC 2.3.1.257). Unlike the ribosome-associated NatA/NatB/NatC/NatE complexes, NAA40 is a monomeric enzyme with a narrow, sequence-specific selectivity restricted to these histone N-termini and recognizes the substrate independently of the bulk Nt-acetylation machinery. NAA40-mediated N-terminal acetylation of H4 influences chromatin function and crosstalk with adjacent histone marks (e.g. H4R3 methylation), and NAA40 has reported roles in transcriptional regulation, ribosomal RNA expression, cellular metabolism (including hepatic lipid metabolism), and as a negative regulator of apoptosis. NAA40 localizes mainly to the nucleus with a cytoplasmic pool.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0010485 histone H4 acetyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of histone H4 acetyltransferase activity, the core, experimentally established function of NAA40 (N-terminal acetylation of histone H4). Reason: NAA40 specifically N-terminally acetylates histone H4; directly demonstrated and conserved across the NatD family. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A |
| GO:0043998 histone H2A acetyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of histone H2A acetyltransferase activity; NAA40 N-terminally acetylates H2A, which shares the H4 N-terminal sequence. Reason: Core, experimentally established histone N-terminal acetylation activity of NAA40. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A |
| GO:1990189 protein N-terminal-serine acetyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: NAA40 acetylates the N-terminal serine of histones H4/H2A; this generic N-terminal serine acetyltransferase MF correctly describes the chemistry, but the histone-specific terms capture the biology more precisely. Reason: NAA40 is an N-terminal serine acetyltransferase (the H4/H2A N-terminus is Ser); the term is correct and complements the histone-specific MFs. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt specifically recognizes the 'Ser-Gly-Arg-Gly sequence' |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: NAA40 acts in the nucleus on chromatin-associated histones H4/H2A. Reason: The nucleus is the site of action for NAA40 histone N-terminal acetylation; well supported. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005634 nucleus cellular_component EXP PMID:25732826 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation of nuclear localization, consistent with NAA40's chromatin substrate. Reason: Correct localization for histone N-terminal acetylation. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005634 nucleus cellular_component EXP PMID:25732826 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation of a cytoplasmic pool of NAA40. Reason: A cytoplasmic pool is documented experimentally but NAA40's core histone-acetylation function is nuclear; kept non-core. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005737 cytoplasm cellular_component EXP PMID:25732826 |
| GO:0006338 chromatin remodeling | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inferred from the histone H4 acetyltransferase MF; N-terminal acetylation of H4 modulates chromatin. The broad "chromatin remodeling" term is a loose fit for a covalent histone-mark-writing activity. Reason: NAA40 writes a histone N-terminal acetyl mark that affects chromatin function/crosstalk, but it is not a canonical ATP-dependent chromatin remodeler; kept as a non-core process annotation. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0006338 chromatin remodeling biological_process IEA GO_REF:0000108 |
| GO:0010485 histone H4 acetyltransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro domain-based electronic annotation of histone H4 acetyltransferase activity, consistent with experimental evidence. Reason: Core activity; redundant with IDA/IBA H4 annotations. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A |
| GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic acyltransferase MF from InterPro; correct but far less informative than the histone N-terminal acetyltransferase terms. Reason: High-level acyltransferase term superseded by the specific histone Nt-acetyltransferase activities. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups molecular_function IEA |
| GO:0043998 histone H2A acetyltransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro domain-based electronic annotation of histone H2A acetyltransferase activity, consistent with experiment. Reason: Core activity; redundant with IDA/IBA H2A annotations. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A |
| GO:1990189 protein N-terminal-serine acetyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: RHEA-derived electronic annotation of N-terminal serine acetyltransferase activity (EC 2.3.1.257), reflecting the histone H4/H2A N-terminal Ser substrate. Reason: Correct chemistry for NAA40; complements the histone-specific terms. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt specifically recognizes the 'Ser-Gly-Arg-Gly sequence' |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: IntAct interaction (histone H2B variant P20290-2) from a high-throughput study. Generic protein binding term. Reason: High-throughput interaction; uninformative as a core MF (histone substrate binding is implicit in the catalytic MF). Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005515 protein binding molecular_function IPI PMID:32296183 UniProtKB:P20290-2 |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence nucleoplasmic localization, consistent with NAA40's chromatin-associated histone substrate. Reason: Correct, specific nuclear localization for histone N-terminal acetylation. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005654 nucleoplasm cellular_component IDA GO_REF:0000052 HPA |
| GO:0005829 cytosol | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence cytosolic pool of NAA40. Reason: A cytosolic pool is documented but the core function is nuclear; kept non-core. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005829 cytosol cellular_component IDA GO_REF:0000052 HPA |
| GO:0005634 nucleus | EXP PMID:25732826 An organellar NΞ±-acetyltransferase, Naa60, acetylates cytoso... | ACCEPT | Summary: Experimental nuclear localization of NAA40. Reason: Core localization for histone N-terminal acetylation. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005634 nucleus cellular_component EXP PMID:25732826 |
| GO:0005737 cytoplasm | EXP PMID:25732826 An organellar NΞ±-acetyltransferase, Naa60, acetylates cytoso... | KEEP AS NON CORE | Summary: Experimental cytoplasmic pool of NAA40. Reason: Documented cytoplasmic pool; non-core relative to nuclear histone acetylation. Supporting Evidence: file:human/NAA40/NAA40-goa.tsv GO:0005737 cytoplasm cellular_component EXP PMID:25732826 |
| GO:0010485 histone H4 acetyltransferase activity | IDA PMID:25619998 The molecular basis for histone H4- and H2A-specific amino-t... | ACCEPT | Summary: Direct biochemical demonstration that NAA40 N-terminally acetylates histone H4; the core catalytic function. Reason: Direct experimental evidence for the defining NAA40 activity. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A |
| GO:0043998 histone H2A acetyltransferase activity | IDA PMID:25619998 The molecular basis for histone H4- and H2A-specific amino-t... | ACCEPT | Summary: Direct biochemical demonstration that NAA40 N-terminally acetylates histone H2A; core catalytic function. Reason: Direct experimental evidence for the defining NAA40 activity. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A |
| GO:1990189 protein N-terminal-serine acetyltransferase activity | IDA PMID:25619998 The molecular basis for histone H4- and H2A-specific amino-t... | ACCEPT | Summary: Direct evidence that NAA40 acetylates the N-terminal serine of its histone substrates; correct chemistry, complementing the histone-specific MFs. Reason: Direct experimental evidence; the H4/H2A N-terminus is Ser, so this term is accurate. Supporting Evidence: file:human/NAA40/NAA40-uniprot.txt specifically recognizes the 'Ser-Gly-Arg-Gly sequence' |
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Download this section (compressed HTML)Q: How does NAA40-mediated N-terminal acetylation of H4/H2A functionally cross-talk with adjacent histone modifications (e.g. H4R3 methylation, H4S1 phosphorylation) to regulate transcription?
Q: To what extent do the reported metabolic and anti-apoptotic phenotypes of NAA40 depend on its histone N-terminal acetyltransferase catalytic activity versus non-catalytic roles?
Experiment: Catalytic-dead NAA40 rescue of an NAA40 knockout to separate histone-acetylation-dependent from independent phenotypes (transcription, rRNA expression, lipid metabolism, apoptosis).
Experiment: Quantitative N-terminal proteomics/ChIP of H4/H2A N-terminal acetylation genome-wide to map where NAA40 marks chromatin and how this changes with metabolic state.
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