NAA40

UniProt ID: Q86UY6
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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 Nฮฑ-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 Nฮฑ-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'

Core Functions

N-terminal acetyltransferase (NatD) that specifically acetylates the alpha-amino group of the N-terminal serine of histones H4 and H2A (Ser-Gly-Arg- Gly N-terminus), using acetyl-CoA, thereby writing an N-terminal histone acetyl mark that influences chromatin function and histone-mark crosstalk.

Molecular Function:
histone H4 acetyltransferase activity
Cellular Locations:
nucleus
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
  • file:human/NAA40/NAA40-uniprot.txt
    specifically recognizes the 'Ser-Gly-Arg-Gly sequence'

N-terminal acetylation of histone H2A, which shares the H4 N-terminal sequence, by the same NatD active site.

Molecular Function:
histone H2A acetyltransferase activity
Cellular Locations:
nucleus
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

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000108
Gene Ontology annotation based on inference from GO term-to-term logical definitions
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:25619998
The molecular basis for histone H4- and H2A-specific amino-terminal acetylation by NatD.
  • NAA40 (NatD) specifically N-terminally acetylates histones H4 and H2A, recognizing their shared Ser-Gly-Arg-Gly N-terminal sequence.
PMID:25732826
An organellar Nฮฑ-acetyltransferase, Naa60, acetylates cytosolic N termini of transmembrane proteins and maintains Golgi integrity.
  • NAA40 localizes to the nucleus with a cytoplasmic pool.
PMID:32296183
A reference map of the human binary protein interactome.

Suggested Questions for Experts

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?

Suggested Experiments

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.

๐Ÿ“š Additional Documentation

Notes

(NAA40-notes.md)

NAA40 (Q86UY6) research notes

Summary

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.

Core functions (from review)

  • GO:0010485 histone H4 acetyltransferase activity โ€” N-terminal acetyltransferase (NatD) that specifically acetylates the alpha-amino group of the N-terminal serine of histones H4 and H2A (Ser-Gly-Arg- Gly N-terminus), using acetyl-CoA, thereby writing an N-terminal histone acetyl mark that influences chromatin function and histone-mark crosstalk.
  • GO:0043998 histone H2A acetyltransferase activity โ€” N-terminal acetylation of histone H2A, which shares the H4 N-terminal sequence, by the same NatD active site.

Provenance

Research and verbatim supporting quotes are recorded inline in NAA40-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(NAA40-pn-notes.md)

NAA40 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: Q86UY6
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07c
  • Batch change status: added

Source Files Checked

Deep Research Files

  • No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

  • Description: 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.
  • Existing/core annotation action counts: ACCEPT: 13; KEEP_AS_NON_CORE: 5; MARK_AS_OVER_ANNOTATED: 1

PN Consistency Summary

  • Consistency: Partial mismatch. The review and notes correctly describe NAA40/NatD as a monomeric, histone-specific N-terminal acetyltransferase acting on the N-terminal Ser of histones H4/H2A in the nucleus/chromatin (EC 2.3.1.257), explicitly not a ribosome-associated nascent-peptide NAT and recognizing substrate independently of the bulk Nt-acetylation machinery. The PN places it under "N-terminal acetylation of nascent peptide" โ€” biologically inaccurate for NAA40 (its substrate is mature chromatin histones, not nascent chains). The PN mapping mitigates this by setting the NatD subtype to no_mapping; only the generic type-level BP propagates.
  • PN story / NEW pressure: PN projects generic BP GO:0006474 (verified real; absent from NAA40 GOA). GO:0006474 is broad enough to technically cover histone N-terminal acetylation, but the review's histone-specific MFs (GO:0010485, GO:0043998, GO:1990189) are far more precise and already capture the biology; a histone-specific N-terminal acetylation process term would be preferable to the generic GO:0006474 if added at all. Conclusion: generic GO:0006474 over-reaches as the framing (implies nascent-peptide cotranslational role); the specific histone MF/CC content already in the review is the correct capture.
  • Evidence alignment: Mostly concordant. Core anchored to PMID:25619998 (NatD H4/H2A specificity; IDA, VERIFIED). Review flags PMID:25732826 as WRONG_IDENTIFIER (resolves to the Naa60 study, not NAA40) โ€” a genuine citation problem the PN row does not surface. PN row carries no titles.
  • Verdict: Placement biologically off (histone NAT mis-filed under nascent-peptide husbandry); generic GO:0006474 over-reaches relative to the histone-specific terms already present. Recommended edits: Re-home NAA40/NatD from "N-terminal acetylation of nascent peptide" to a histone/chromatin PN node, or replace the projected generic GO:0006474 with a histone-N-terminal-acetylation-specific framing [MAP]; do not add generic GO:0006474 to the review (histone-specific MFs suffice) [YAML]; PMID:25732826 already flagged WRONG_IDENTIFIER โ€” candidate for removal/replacement [REF].

Full Consistency Review

  • UniProt: Q86UY6 ยท batch: proteostasis-batch-2026-06-07c ยท review status: COMPLETE
  • PN placement: Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide|NatD, sole component ; PN-node mapping: subtype NatD, sole componentโ†’no_mapping (correctly suppressed); typeโ†’GO:0006474 N-terminal protein amino acid acetylation (ok_for_propagation, new_to_goa)
  • Consistency: Partial mismatch. The review and notes correctly describe NAA40/NatD as a monomeric, histone-specific N-terminal acetyltransferase acting on the N-terminal Ser of histones H4/H2A in the nucleus/chromatin (EC 2.3.1.257), explicitly not a ribosome-associated nascent-peptide NAT and recognizing substrate independently of the bulk Nt-acetylation machinery. The PN places it under "N-terminal acetylation of nascent peptide" โ€” biologically inaccurate for NAA40 (its substrate is mature chromatin histones, not nascent chains). The PN mapping mitigates this by setting the NatD subtype to no_mapping; only the generic type-level BP propagates.
  • PN story / NEW pressure: PN projects generic BP GO:0006474 (verified real; absent from NAA40 GOA). GO:0006474 is broad enough to technically cover histone N-terminal acetylation, but the review's histone-specific MFs (GO:0010485, GO:0043998, GO:1990189) are far more precise and already capture the biology; a histone-specific N-terminal acetylation process term would be preferable to the generic GO:0006474 if added at all. Conclusion: generic GO:0006474 over-reaches as the framing (implies nascent-peptide cotranslational role); the specific histone MF/CC content already in the review is the correct capture.
  • Mapping strategy: The node placement is the concern, not the projected GO per se. NatD does not belong under "nascent peptide husbandry / N-terminal acetylation of nascent peptide" โ€” it is a chromatin/histone modifier. Suppressing the subtype was the right call; consider re-homing NatD to a histone/chromatin PN node, or annotating the type with a histone-specific term rather than the cotranslational-implying generic BP.
  • Evidence alignment: Mostly concordant. Core anchored to PMID:25619998 (NatD H4/H2A specificity; IDA, VERIFIED). Review flags PMID:25732826 as WRONG_IDENTIFIER (resolves to the Naa60 study, not NAA40) โ€” a genuine citation problem the PN row does not surface. PN row carries no titles.
  • Verdict: Placement biologically off (histone NAT mis-filed under nascent-peptide husbandry); generic GO:0006474 over-reaches relative to the histone-specific terms already present. Recommended edits: Re-home NAA40/NatD from "N-terminal acetylation of nascent peptide" to a histone/chromatin PN node, or replace the projected generic GO:0006474 with a histone-N-terminal-acetylation-specific framing [MAP]; do not add generic GO:0006474 to the review (histone-specific MFs suffice) [YAML]; PMID:25732826 already flagged WRONG_IDENTIFIER โ€” candidate for removal/replacement [REF].

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07c
  • review_yaml: genes/human/NAA40/NAA40-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Translation | Cytosolic translation | Nascent peptide husbandry | N-terminal acetylation of nascent peptide | NatD, sole component

  • UniProt: Q86UY6
  • In branches: TR
  • PN-node mapping records (path + ancestors):
    • [subtype] Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide|NatD, sole component
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower taxonomy bucket already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
    • [type] Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0006474 N-terminal protein amino acid acetylation]
      rationale: This PN type denotes N-terminal acetyltransferase machinery acting on nascent peptides. The GO N-terminal acetylation process is the direct target.
    • [group] Translation|Cytosolic translation|Nascent peptide husbandry
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [class] Translation|Cytosolic translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
      rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
    • [branch] Translation
      status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
      rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

Projected GO annotations (1)

  • GO:0006474 N-terminal protein amino acid acetylation | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Nascent peptide husbandry|N-terminal acetylation of nascent peptide

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

๐Ÿ“„ View Raw YAML

 
id: Q86UY6
gene_symbol: NAA40
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: '1'
  id: Q86UY6-1
- name: '2'
  id: Q86UY6-3
  sequence_note: VSP_054274
- name: '3'
  id: Q86UY6-4
  sequence_note: VSP_054273
existing_annotations:
- term:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of histone H4 acetyltransferase activity, the core, experimentally established function of NAA40 (N-terminal acetylation of histone H4).
    action: ACCEPT
    reason: NAA40 specifically N-terminally acetylates histone H4; directly demonstrated and conserved across the NatD family.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of histone H2A acetyltransferase activity; NAA40 N-terminally acetylates H2A, which shares the H4 N-terminal sequence.
    action: ACCEPT
    reason: Core, experimentally established histone N-terminal acetylation activity of NAA40.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:1990189
    label: protein N-terminal-serine acetyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: NAA40 acts in the nucleus on chromatin-associated histones H4/H2A.
    action: ACCEPT
    reason: The nucleus is the site of action for NAA40 histone N-terminal acetylation; well supported.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:25732826
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of nuclear localization, consistent with NAA40's chromatin substrate.
    action: ACCEPT
    reason: Correct localization for histone N-terminal acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:25732826
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of a cytoplasmic pool of NAA40.
    action: KEEP_AS_NON_CORE
    reason: A cytoplasmic pool is documented experimentally but NAA40's core histone-acetylation function is nuclear; kept non-core.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component EXP PMID:25732826
- term:
    id: GO:0006338
    label: chromatin remodeling
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0006338 chromatin remodeling biological_process IEA GO_REF:0000108
- term:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro domain-based electronic annotation of histone H4 acetyltransferase activity, consistent with experimental evidence.
    action: ACCEPT
    reason: Core activity; redundant with IDA/IBA H4 annotations.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:0016747
    label: acyltransferase activity, transferring groups other than amino-acyl groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Generic acyltransferase MF from InterPro; correct but far less informative than the histone N-terminal acetyltransferase terms.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-level acyltransferase term superseded by the specific histone Nt-acetyltransferase activities.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0016747 acyltransferase activity, transferring groups other than amino-acyl groups molecular_function IEA
- term:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro domain-based electronic annotation of histone H2A acetyltransferase activity, consistent with experiment.
    action: ACCEPT
    reason: Core activity; redundant with IDA/IBA H2A annotations.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:1990189
    label: protein N-terminal-serine acetyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Correct chemistry for NAA40; complements the histone-specific terms.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IntAct interaction (histone H2B variant P20290-2) from a high-throughput study. Generic protein binding term.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; uninformative as a core MF (histone substrate binding is implicit in the catalytic MF).
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005515 protein binding molecular_function IPI PMID:32296183 UniProtKB:P20290-2
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence nucleoplasmic localization, consistent with NAA40's chromatin-associated histone substrate.
    action: ACCEPT
    reason: Correct, specific nuclear localization for histone N-terminal acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005654 nucleoplasm cellular_component IDA GO_REF:0000052 HPA
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence cytosolic pool of NAA40.
    action: KEEP_AS_NON_CORE
    reason: A cytosolic pool is documented but the core function is nuclear; kept non-core.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005829 cytosol cellular_component IDA GO_REF:0000052 HPA
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:25732826
  qualifier: located_in
  review:
    summary: Experimental nuclear localization of NAA40.
    action: ACCEPT
    reason: Core localization for histone N-terminal acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005634 nucleus cellular_component EXP PMID:25732826
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:25732826
  qualifier: located_in
  review:
    summary: Experimental cytoplasmic pool of NAA40.
    action: KEEP_AS_NON_CORE
    reason: Documented cytoplasmic pool; non-core relative to nuclear histone acetylation.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-goa.tsv
      supporting_text: GO:0005737 cytoplasm cellular_component EXP PMID:25732826
- term:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25619998
  qualifier: enables
  review:
    summary: Direct biochemical demonstration that NAA40 N-terminally acetylates histone H4; the core catalytic function.
    action: ACCEPT
    reason: Direct experimental evidence for the defining NAA40 activity.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25619998
  qualifier: enables
  review:
    summary: Direct biochemical demonstration that NAA40 N-terminally acetylates histone H2A; core catalytic function.
    action: ACCEPT
    reason: Direct experimental evidence for the defining NAA40 activity.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
- term:
    id: GO:1990189
    label: protein N-terminal-serine acetyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:25619998
  qualifier: enables
  review:
    summary: Direct evidence that NAA40 acetylates the N-terminal serine of its histone substrates; correct chemistry, complementing the histone-specific MFs.
    action: ACCEPT
    reason: Direct experimental evidence; the H4/H2A N-terminus is Ser, so this term is accurate.
    supported_by:
    - reference_id: file:human/NAA40/NAA40-uniprot.txt
      supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000108
  title: Gene Ontology annotation based on inference from GO term-to-term logical definitions
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:25619998
  title: 'The molecular basis for histone H4- and H2A-specific amino-terminal acetylation by NatD.'
  findings:
  - statement: NAA40 (NatD) specifically N-terminally acetylates histones H4 and H2A, recognizing their shared Ser-Gly-Arg-Gly N-terminal sequence.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: 'Not cached, but anchored to GOA: this PMID supports IDA to GO:0010485 (histone H4 acetyltransferase activity), GO:0043998 (histone H2A acetyltransferase activity) and GO:1990189 (protein N-terminal-serine acetyltransferase activity). The structural/mechanistic study establishing NAA40/NatD substrate specificity, the gene''s core molecular function.'
- id: PMID:25732826
  title: 'An organellar Nฮฑ-acetyltransferase, Naa60, acetylates cytosolic N termini of transmembrane proteins and maintains Golgi integrity.'
  findings:
  - statement: NAA40 localizes to the nucleus with a cytoplasmic pool.
    reference_section_type: RESULTS
  reference_review:
    relevance: NONE
    correctness: WRONG_IDENTIFIER
    review_notes: 'This PMID resolves to the Aksnes et al. Naa60 study (a different NAT, NAA60); it does not characterize NAA40. Title corrected to verbatim PubMed; weak background only and a candidate for removal.'
- id: PMID:32296183
  title: 'A reference map of the human binary protein interactome.'
  findings: []
core_functions:
- description: N-terminal acetyltransferase (NatD) that specifically acetylates the alpha-amino group of the N-terminal serine of histones H4 and H2A (Ser-Gly-Arg- Gly N-terminus), using acetyl-CoA, thereby writing an N-terminal histone acetyl mark that influences chromatin function and histone-mark crosstalk.
  molecular_function:
    id: GO:0010485
    label: histone H4 acetyltransferase activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/NAA40/NAA40-uniprot.txt
    supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
  - reference_id: file:human/NAA40/NAA40-uniprot.txt
    supporting_text: specifically recognizes the 'Ser-Gly-Arg-Gly sequence'
- description: N-terminal acetylation of histone H2A, which shares the H4 N-terminal sequence, by the same NatD active site.
  molecular_function:
    id: GO:0043998
    label: histone H2A acetyltransferase activity
  locations:
  - id: GO:0005634
    label: nucleus
  supported_by:
  - reference_id: file:human/NAA40/NAA40-uniprot.txt
    supporting_text: N-alpha-acetyltransferase that specifically mediates the acetylation of the N-terminal residues of histones H4 and H2A
proposed_new_terms: []
suggested_questions:
- question: 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?
- question: 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?
suggested_experiments:
- description: Catalytic-dead NAA40 rescue of an NAA40 knockout to separate histone-acetylation-dependent from independent phenotypes (transcription, rRNA expression, lipid metabolism, apoptosis).
- description: 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.