Affinage

NAA80

N-alpha-acetyltransferase 80 · UniProt Q93015

Length
286 aa
Mass
31.4 kDa
Annotated
2026-04-29
16 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NAA80 is the dedicated posttranslational N-terminal acetyltransferase for actin, catalyzing the final maturation step of all actin isoforms by acetylating their processed N-termini. It adopts a GNAT fold with an unusually open substrate-binding region that recognizes acidic residues at positions 2–3 of actin N-termini, and forms a ternary complex with G-actin and its activating cofactor PFN2 via a proline-rich loop, which enhances catalytic efficiency (PMID:29581307, PMID:32978259). Loss of NAA80 increases the F/G-actin ratio, accelerates cell motility, disrupts Golgi apparatus integrity, and impairs hearing in zebrafish, establishing actin Nt-acetylation as critical for cytoskeletal homeostasis and organelle organization (PMID:29581253, PMID:32209306, PMID:39384430). Biallelic loss-of-function NAA80 variants in humans recapitulate these cellular phenotypes in patient-derived fibroblasts, linking NAA80 deficiency to a neurodevelopmental disorder (PMID:34805998).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2000 Medium

    NAA80 was first shown to possess intrinsic N-terminal acetyltransferase activity operating via a ping-pong mechanism, establishing it as a cytoplasmic NAT enzyme before its physiological substrate was known.

    Evidence In vitro acetyltransferase assay and GFP-tag localization in cultured cells

    PMID:10644992

    Open questions at the time
    • Physiological substrate unidentified
    • Single-lab characterization without independent replication at the time
    • Mechanism of substrate selectivity unknown
  2. 2018 High

    Three independent studies converged to identify actin as the specific physiological substrate of NAA80, demonstrating that NAA80 knockout abolishes actin Nt-acetylation across multiple isoforms and that its GNAT fold recognizes acidic residues at positions 2–3 of the actin N-terminus, resolving the long-standing question of which enzyme acetylates actin.

    Evidence Crystal structure with bisubstrate inhibitor, NAA80-KO human cell lines with rescue, in vitro acetylation assays on purified actins and peptides, actin polymerization/depolymerization kinetics

    PMID:29581253 PMID:29581307 PMID:30028079

    Open questions at the time
    • How NAA80 is recruited to newly processed G-actin in vivo remained unclear
    • No cofactor or regulatory partner yet identified
    • Structural basis for full-length actin recognition beyond N-terminal peptide not resolved
  3. 2020 High

    Identification of PFN2 as a stable activating cofactor that binds NAA80's proline-rich loop and forms a ternary complex with G-actin answered how NAA80 achieves efficient substrate engagement, while the discovery that NAA80 loss fragments the Golgi apparatus extended its functional impact beyond actin dynamics to organelle integrity.

    Evidence AP-MS interaction proteomics, analytical ultracentrifugation, SAXS, deletion mutagenesis, catalytic-dead mutant rescue of Golgi phenotype

    PMID:32209306 PMID:32978259

    Open questions at the time
    • Whether PFN1 can substitute for PFN2 not fully resolved
    • Structural model of the full ternary complex at atomic resolution not available
    • Mechanism linking actin Nt-acetylation to Golgi membrane organization not elucidated
  4. 2021 High

    Targeted proteomics established NAA80-mediated acetylation as the definitive terminal modification of β-actin by disproving the existence of Nt-arginylated β-actin in wildtype cells, and human genetic studies linked biallelic NAA80 loss-of-function variants to a neurodevelopmental phenotype with cellular hallmarks matching KO models.

    Evidence Targeted mass spectrometry in NAA80-KO cells, patient-derived fibroblasts from individuals with biallelic NAA80 variants with migration, filopodia, and F-actin assays

    PMID:34805998 PMID:34896361

    Open questions at the time
    • Number of identified patients is small; full clinical spectrum not delineated
    • Whether residual actin acetylation in patient cells reflects hypomorphic alleles or alternative enzymes is unclear
    • Relationship between actin acetylation loss and neurodevelopmental pathology not mechanistically dissected
  5. 2024 High

    A zebrafish knockout model demonstrated that NAA80-dependent actin acetylation is required for inner ear development and hearing, extending the in vivo physiological roles of this modification to sensory organ function.

    Evidence Zebrafish naa80 KO with inner ear morphology analysis, otolith assessment, and auditory behavioral assays

    PMID:39384430

    Open questions at the time
    • Whether hearing defects arise from stereocilia actin dysfunction or broader developmental disruption is unresolved
    • Mammalian auditory phenotype not yet demonstrated
    • Tissue-specific requirements for actin Nt-acetylation not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of the NAA80–PFN2–actin ternary complex, the molecular mechanism by which Nt-acetylation modulates actin filament dynamics and Golgi organization, and whether NAA80 loss underlies a defined human Mendelian syndrome with consistent clinical features.
  • No high-resolution structure of the full ternary complex
  • Biophysical mechanism connecting Nt-acetylation to altered depolymerization and formin-driven elongation rates not determined
  • Full genotype-phenotype spectrum in humans remains to be established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 7
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 3
Partners
ACTA1ACTBACTG1PFN2

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 NAA80 is the N-terminal acetyltransferase (NAT) that posttranslationally Nt-acetylates actin. Absence of NAA80-mediated Nt-acetylation alters actin filament depolymerization and elongation rates (including formin-driven elongation), while filament nucleation by the Arp2/3 complex is mostly unaffected. NAA80-knockout cells display increased F/G-actin ratio, increased filopodia and lamellipodia formation, and accelerated cell motility. In vitro acetylation assays, NAA80-knockout cell lines, actin polymerization/depolymerization kinetics assays, live-cell imaging, cellular morphology analysis Proceedings of the National Academy of Sciences of the United States of America High 29581253
2018 Crystal structure of NAA80 in complex with a bisubstrate inhibitor reveals that NAA80 adopts a GNAT fold similar to other NAT enzymes but with a more open substrate-binding region. Substrate specificity is determined primarily by interactions with acidic residues at positions 2 and 3 of the actin N-terminus (not positions 1 and 2 as in most NATs). Ectopic expression of NAA80 in yeast lacking NatB partially restored Nt-acetylation of NatB substrates including yeast actin, demonstrating intrinsic posttranslational NAT capacity. X-ray crystallography, bisubstrate inhibitor development, yeast complementation model, in vitro acetylation assays Proceedings of the National Academy of Sciences of the United States of America High 29581307
2018 NAA80 (NAT6/Fus2) is the enzyme that acetylates the N-terminal acidic residue of multiple mammalian actin isoforms (β-actin Asp2, γ-actin-1 Glu2, α-actin-1). Knockout of NAA80 in human cell lines abolishes this acetylation, and re-expression of NAA80 fully restores it, while NAA10 shows little or no activity on actin substrates. Recombinant enzyme activity assays on purified proteins and peptides, NAA80-knockout cell lines, re-expression rescue, comparison with NAA10 activity The FEBS journal High 30028079
2020 PFN2 (profilin 2) is a stable interaction partner of NAA80 identified by interaction proteomics and confirmed by analytical ultracentrifugation. PFN2 binding to a proline-rich loop of NAA80 specifically increases NAA80's intrinsic catalytic activity. Small-angle X-ray scattering shows NAA80, actin, and PFN2 form a ternary complex. Deletion of the proline-rich loop abrogates PFN2 binding and reduces acetylation efficiency. The majority of cellular NAA80 is stably bound to PFN2, suggesting the PFN2–NAA80 complex acetylates G-actin before filament incorporation. Interaction proteomics (AP-MS), analytical ultracentrifugation, enzyme activity assays, SAXS, deletion mutagenesis, co-immunoprecipitation The Journal of biological chemistry High 32978259
2000 NAA80 (Fus-2) possesses acetyltransferase activity, acetylating protein N-termini via a ping-pong mechanism with substrate specificity, and localizes to the cytoplasm as shown by GFP-tagging experiments. In vitro acetyltransferase assay, GFP-tag subcellular localization, sequence homology analysis Oncogene Medium 10644992
2021 NAA80-mediated Nt-acetylation is the terminal maturation step of β-actin; targeted proteomics in NAA80-lacking cells demonstrated that previously claimed Nt-arginylated β-actin (RDDI-) does not exist at detectable levels in wildtype cells, and only minimal arginylation of unacetylated β-actin (DDDI-) is detectable in NAA80-KO cells, establishing NAA80 as the definitive finalizer of β-actin N-terminal maturation. Targeted mass spectrometry proteomics, NAA80-knockout cells, comparison with ATE1 arginylation antibody assay Journal of molecular biology High 34896361
2020 NAA80-knockout cells display Golgi apparatus fragmentation and increased Golgi dynamics. Re-expression of catalytically active NAA80 (restoring actin Nt-acetylation) rescues Golgi structure, whereas a catalytic dead NAA80 mutant cannot, establishing that NAA80's acetyltransferase activity toward actin is required for maintaining Golgi integrity. This is linked to a drastic increase in F-actin levels in NAA80 KO cells. NAA80-knockout cell lines, rescue with wildtype vs. catalytic dead NAA80 mutant, live-cell imaging, F-actin quantification Experimental cell research High 32209306
2021 Homozygous loss-of-function NAA80 variants in humans cause ~50% reduction in actin N-terminal acetylation, with patient-derived fibroblasts showing increased migration, increased filopodia counts, and increased polymerized actin levels, consistent with NAA80-KO cell phenotypes and establishing NAA80's role in controlling actin dynamics in vivo. Patient-derived fibroblasts and PBMCs from individuals with bi-allelic NAA80 variants, actin acetylation quantification, cell migration assay, filopodia counting, F-actin measurement, structural modeling of destabilizing variant Brain communications High 34805998
2024 Zebrafish Naa80 N-terminally acetylates both muscle and non-muscle actins in vivo. Naa80 knockout zebrafish exhibit impaired inner ear development, small otoliths, and defective response to sound, demonstrating that actin N-terminal acetylation by NAA80 is essential for normal hearing. Zebrafish naa80 knockout model, in vitro acetylation assays with purified Naa80, mass spectrometry-based acetylation quantification, inner ear morphology analysis, auditory behavioral assays Life science alliance High 39384430

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 NAA80 is actin's N-terminal acetyltransferase and regulates cytoskeleton assembly and cell motility. Proceedings of the National Academy of Sciences of the United States of America 160 29581253
2018 Structural determinants and cellular environment define processed actin as the sole substrate of the N-terminal acetyltransferase NAA80. Proceedings of the National Academy of Sciences of the United States of America 62 29581307
1995 Fus2 localizes near the site of cell fusion and is required for both cell fusion and nuclear alignment during zygote formation. The Journal of cell biology 60 7559752
2018 NAT6 acetylates the N-terminus of different forms of actin. The FEBS journal 39 30028079
2002 Characterization of the murine hyaluronidase gene region reveals complex organization and cotranscription of Hyal1 with downstream genes, Fus2 and Hyal3. The Journal of biological chemistry 30 11929860
2020 PFN2 and NAA80 cooperate to efficiently acetylate the N-terminus of actin. The Journal of biological chemistry 26 32978259
2021 NAA80 bi-allelic missense variants result in high-frequency hearing loss, muscle weakness and developmental delay. Brain communications 24 34805998
2018 Actin polymerization and cell motility are affected by NAA80-mediated posttranslational N-terminal acetylation of actin. Communicative & integrative biology 18 30534344
2021 The Final Maturation State of β-actin Involves N-terminal Acetylation by NAA80, not N-terminal Arginylation by ATE1. Journal of molecular biology 16 34896361
2020 N-terminal acetylation of actin by NAA80 is essential for structural integrity of the Golgi apparatus. Experimental cell research 12 32209306
2000 The putative tumour suppressor Fus-2 is an N-acetyltransferase. Oncogene 11 10644992
2004 Characterization of a new SNP c767A/T (Arg222Trp) in the candidate TSG FUS2 on human chromosome 3p21.3: prevalence in Asian populations and analysis of association with nasopharyngeal cancer. Molecular and cellular probes 3 15036368
2024 Naa80 is required for actin N-terminal acetylation and normal hearing in zebrafish. Life science alliance 2 39384430
2023 Optimized bisubstrate inhibitors for the actin N-terminal acetyltransferase NAA80. Frontiers in chemistry 2 37408560
2004 Structural and expression analysis of the porcine FUS2 gene. Gene 2 15276206
2006 [SNP767A/T of FUS2 gene and lung cancer risk in Chinese population]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 21176460