id: Q5VZE5 gene_symbol: NAA35 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: NAA35 (N-alpha-acetyltransferase 35; also MAK10, EGAP) is the large non-catalytic auxiliary/scaffold subunit of the human NatC N-terminal acetyltransferase complex (NatC = NAA30 catalytic + NAA35 + NAA38). It does not itself catalyze acetyl transfer; instead it scaffolds the complex and is required for NatC function and integrity. NatC co-translationally acetylates the alpha-amino group of N-terminal methionine residues retained in front of bulky/hydrophobic residues, a modification that shields substrates from N-degron-mediated ubiquitination and degradation. NAA35 is predominantly cytoplasmic and ribosome-associated. Loss of NatC subunits triggers p53-dependent apoptosis, and the mouse ortholog (EGAP) has been linked to smooth-muscle-cell proliferation and embryonic vascular development. alternative_products: - name: '1' id: Q5VZE5-1 - name: '2' id: Q5VZE5-2 sequence_note: VSP_056098, VSP_056099 existing_annotations: - term: id: GO:0031417 label: NatC complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: NAA35 is a constitutive auxiliary subunit of the NatC complex; phylogenetic inference across MAK10 orthologs supports this membership, which is also directly demonstrated. Structural work (Grunwald 2020) shows NAA35 is the central scaffold that wraps around both NAA30 and NAA38 to hold the heterotrimer together. action: ACCEPT reason: NatC complex membership is the defining cellular component of NAA35 and is well supported by phylogenetic and direct experimental evidence. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: Component of the N-terminal acetyltransferase C (NatC) complex, which is composed of NAA35, NAA38 and NAA30. - reference_id: file:human/NAA35/NAA35-deep-research-falcon.md supporting_text: NAA35's primary role is to serve as the central assembly scaffold that organizes the NatC complex architecture and mediates its interaction with ribosomes, thereby enabling co-translational N-terminal acetylation of specific substrate proteins - term: id: GO:0043066 label: negative regulation of apoptotic process evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Knockdown of NatC subunits (including NAA35) induces p53-dependent apoptosis, implying that NatC activity normally suppresses apoptosis. This is a downstream biological-process consequence of NatC-mediated N-terminal acetylation, not a direct molecular activity of NAA35. action: KEEP_AS_NON_CORE reason: Plausible process annotation derived from the apoptotic phenotype of NatC depletion; indirect and downstream of the complex's core acetyltransferase activity. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: Involved in regulation of apoptosis and proliferation of smooth muscle cells - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Electronic annotation of cytoplasmic localization, consistent with the experimentally documented cytoplasmic site of NatC. action: ACCEPT reason: Cytoplasm is the principal, experimentally supported compartment of NatC. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0031417 label: NatC complex evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: part_of review: summary: InterPro-based electronic annotation of NatC complex membership, redundant with and consistent with stronger experimental evidence. action: ACCEPT reason: Correct and well-corroborated NatC complex membership. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: Component of the N-terminal acetyltransferase C (NatC) complex, which is composed of NAA35, NAA38 and NAA30. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19398576 qualifier: enables review: summary: IntAct interactions with NAA30 (Q147X3) and NAA38 (Q9BRA0), the other NatC subunits. The bare protein binding term is uninformative; the relevant interaction is NatC complex assembly. action: KEEP_AS_NON_CORE reason: Records genuine intra-complex interactions but the uninformative GO:0005515 term is non-core; NatC complex membership captures the meaningful content. supported_by: - reference_id: file:human/NAA35/NAA35-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:19398576 UniProtKB:Q147X3 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Binary yeast two-hybrid interactome (HuRI) interaction with TRIM7 (Q9C029), an E3 ligase unrelated to NatC function. An isolated high-throughput interaction that does not inform NAA35's core role. action: KEEP_AS_NON_CORE reason: Bare protein binding from a single high-throughput binary screen with a partner (TRIM7) outside the NatC complex; uninformative and not part of the core function. supported_by: - reference_id: file:human/NAA35/NAA35-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:32296183 UniProtKB:Q9C029 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex interactome interactions with NAA30 (Q147X3) and NAA38 (Q9BRA0). Uninformative bare protein binding term reflecting NatC complex assembly. action: KEEP_AS_NON_CORE reason: Real interactions with the other NatC subunits; non-core as a bare protein binding annotation, subsumed by the NatC complex term. supported_by: - reference_id: file:human/NAA35/NAA35-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:33961781 UniProtKB:Q147X3 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:40205054 qualifier: enables review: summary: Multimodal cell-maps interactome interaction with NAA30 (Q147X3). Uninformative bare protein binding term reflecting NatC complex assembly. action: KEEP_AS_NON_CORE reason: Real interaction with the NAA30 catalytic subunit; non-core as a bare protein binding annotation, subsumed by the NatC complex term. supported_by: - reference_id: file:human/NAA35/NAA35-goa.tsv supporting_text: GO:0005515 protein binding molecular_function ECO:0000353 IPI PMID:40205054 UniProtKB:Q147X3 - term: id: GO:0048659 label: smooth muscle cell proliferation evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Electronic annotation transferred from the mouse ortholog (EGAP), which was implicated in smooth-muscle-cell proliferation and embryonic vascular development. This is a peripheral, organism-specific developmental role. action: KEEP_AS_NON_CORE reason: Transferred from mouse phenotype data; peripheral to NAA35's core NatC scaffold function and not a direct molecular activity. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: Involved in regulation of apoptosis and proliferation of smooth muscle cells - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Direct immunofluorescence (HPA) evidence for cytosolic localization, consistent with the cytoplasmic site of NatC. action: ACCEPT reason: IDA-supported cytosolic localization matching the cytoplasmic ribosome-associated site of NatC. supported_by: - reference_id: file:human/NAA35/NAA35-goa.tsv supporting_text: GO:0005829 cytosol cellular_component ECO:0000314 IDA GO_REF:0000052 - term: id: GO:0005737 label: cytoplasm evidence_type: NAS original_reference_id: PMID:19398576 qualifier: located_in review: summary: Non-traceable author statement (ComplexPortal) of cytoplasmic localization, consistent with the documented cytoplasmic site of NatC. action: ACCEPT reason: Consistent with the primary cytoplasmic localization of NatC. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0031417 label: NatC complex evidence_type: IPI original_reference_id: PMID:19398576 qualifier: part_of review: summary: ComplexPortal/IPI evidence that NAA35 is part of the NatC complex, from the study that identified the human NatC complex. action: ACCEPT reason: Direct experimental support for NatC complex membership. supported_by: - reference_id: PMID:19398576 supporting_text: the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31 - term: id: GO:0031417 label: NatC complex evidence_type: IDA original_reference_id: PMID:37891180 qualifier: part_of review: summary: Direct experimental confirmation of NatC complex membership in the protein-shielding/longevity study. action: ACCEPT reason: Well-supported NatC complex membership. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: Component of the N-terminal acetyltransferase C (NatC) complex, which is composed of NAA35, NAA38 and NAA30. - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:19398576 qualifier: located_in review: summary: Direct experimental cytoplasmic localization of NAA35, consistent with ribosome-associated NatC activity. NAA35 in particular carries the principal ribosome-binding surface of NatC (an electropositive C-terminal tip region), so its cytoplasmic localization reflects co-translational action at the ribosome. action: ACCEPT reason: Cytoplasm is the principal experimentally supported compartment of NatC. supported_by: - reference_id: PMID:19398576 supporting_text: This complex associates with ribosomes - reference_id: file:human/NAA35/NAA35-deep-research-falcon.md supporting_text: NAA35, as part of the NatC complex, localizes to ribosomes where it functions co-translationally - term: id: GO:0031417 label: NatC complex evidence_type: IDA original_reference_id: PMID:19398576 qualifier: part_of review: summary: Direct experimental identification of NAA35 (hMak10) as an auxiliary subunit of the human NatC complex. action: ACCEPT reason: Defining cellular component, directly demonstrated. supported_by: - reference_id: PMID:19398576 supporting_text: the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31 - term: id: GO:0043066 label: negative regulation of apoptotic process evidence_type: IMP original_reference_id: PMID:19398576 qualifier: involved_in review: summary: Mutant-phenotype evidence that NAA35 (hMak10) knockdown induces p53-dependent apoptosis, indicating NatC normally suppresses apoptosis. Downstream consequence of complex function. action: KEEP_AS_NON_CORE reason: Real phenotype-based process annotation, but indirect and downstream of NatC's core acetyltransferase activity. supported_by: - reference_id: PMID:19398576 supporting_text: results in p53-dependent cell death - term: id: GO:0005737 label: cytoplasm evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity-based annotation of cytoplasmic localization (from mouse ortholog), consistent with the documented cytoplasmic site of NatC. action: ACCEPT reason: Consistent with the primary cytoplasmic localization of NatC; corroborated by IDA evidence. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm' - term: id: GO:0048659 label: smooth muscle cell proliferation evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Sequence-similarity-based annotation transferred from the mouse ortholog (EGAP) linked to smooth-muscle-cell proliferation and embryonic vascular development; a peripheral developmental role. action: KEEP_AS_NON_CORE reason: Transferred from mouse phenotype data; peripheral to NAA35's core NatC scaffold function. supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: Involved in regulation of apoptosis and proliferation of smooth muscle cells - term: id: GO:0006474 label: N-terminal protein amino acid acetylation evidence_type: IC original_reference_id: PMID:19398576 qualifier: involved_in review: summary: NAA35/hMak10 is a non-catalytic auxiliary/scaffold subunit of human NatC, the complex responsible for cotranslational N-terminal acetylation. The acetyltransferase activity resides exclusively in the catalytic NAA30 subunit (GNAT fold); NAA35 contributes the scaffold and part of the NAA30-NAA35 substrate-binding interface but does not itself transfer the acetyl group. The involved_in (process) annotation is therefore appropriate, whereas a catalytic molecular-function term for NAA35 would not be. action: NEW reason: The review captures NatC complex membership but not the BP carried out by that complex. This recommends process involvement for the auxiliary subunit while explicitly not assigning catalytic acetyltransferase MF to NAA35. supported_by: - reference_id: PMID:19398576 supporting_text: the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31 reference_section_type: ABSTRACT - reference_id: PMID:19398576 supporting_text: the human NatC complex functions in cotranslational N-terminal acetylation reference_section_type: ABSTRACT - reference_id: file:human/NAA35/NAA35-deep-research-falcon.md supporting_text: It is crucial to emphasize that NAA35 itself does not possess catalytic acetyltransferase activity. The catalytic function resides exclusively in the NAA30 subunit, which contains the conserved GNAT (GCN5-related N-acetyltransferase) fold references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:19398576 title: Knockdown of human N alpha-terminal acetyltransferase complex C leads to p53-dependent apoptosis and aberrant human Arl8b localization. findings: - statement: NatC contains the catalytic subunit hMak3 (NAA30) and auxiliary subunits hMak10 (NAA35) and hMak31 (NAA38); the complex associates with ribosomes. reference_section_type: ABSTRACT - statement: Knockdown of NatC subunits results in p53-dependent cell death, indicating NatC normally suppresses apoptosis. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached publication title matches the YAML title; GOA anchors this PMID to IDA for GO:0031417 (NatC complex) and IMP for GO:0043066 (negative regulation of apoptosis) for NAA35. This is the NatC complex-characterization paper establishing NAA35 (hMak10) as an auxiliary/scaffold subunit, the gene's core function. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:37891180 title: N-terminal acetylation shields proteins from degradation and promotes age-dependent motility and longevity. findings: - statement: NatC-mediated N-terminal acetylation shields substrate proteins from degradation, promoting protein stabilization, motility and longevity. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Cached publication title matches the YAML title; GOA anchors this PMID to IDA for GO:0031417 (NatC complex). Supports the biological significance of the NatC complex of which NAA35 is the auxiliary subunit. - id: PMID:40205054 title: Multimodal cell maps as a foundation for structural and functional genomics. findings: [] - id: file:human/NAA35/NAA35-deep-research-falcon.md title: Falcon deep research report for NAA35 findings: - statement: NAA35 is the large non-catalytic auxiliary/scaffold subunit of the heterotrimeric NatC complex (with catalytic NAA30 and small auxiliary NAA38); it organizes the complex architecture, contributes to the NAA30-NAA35 substrate-binding interface that determines Met-hydrophobic specificity, and mediates ribosome association via an electropositive C-terminal tip region. reference_review: relevance: HIGH correctness: UNVERIFIED review_notes: 'LLM-synthesized deep-research report. It correctly and repeatedly states that NAA35 does NOT itself catalyze N-terminal acetylation and that catalysis resides exclusively in NAA30 (GNAT fold); NAA35''s role is architectural/scaffolding and ribosome-binding. No mis-attribution of catalytic acetyltransferase activity to the auxiliary subunit was detected. Underlying primary sources (Grunwald 2020 NatC crystal structure; Varland 2023 N-degron shielding) are consistent with the NatC literature, but the specific structural/genetic-interaction claims were not independently verified against full text here, so correctness is left UNVERIFIED.' core_functions: - description: Non-catalytic auxiliary/scaffold subunit of the NatC N-terminal acetyltransferase complex, required for assembly and function of NatC, which co-translationally acetylates N-terminal methionine residues of substrates with bulky/hydrophobic second residues. locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/NAA35/NAA35-uniprot.txt supporting_text: Component of the N-terminal acetyltransferase C (NatC) complex, which is composed of NAA35, NAA38 and NAA30. - reference_id: PMID:19398576 supporting_text: the catalytic subunit hMak3 and the auxiliary subunits hMak10 and hMak31 - reference_id: file:human/NAA35/NAA35-deep-research-falcon.md supporting_text: NAA35's primary role is to serve as the central assembly scaffold that organizes the NatC complex architecture and mediates its interaction with ribosomes, thereby enabling co-translational N-terminal acetylation of specific substrate proteins in_complex: id: GO:0031417 label: NatC complex directly_involved_in: - id: GO:0006474 label: N-terminal protein amino acid acetylation proposed_new_terms: [] suggested_questions: - question: Does the NAA35/Mak10 scaffold mediate ribosome anchoring of NatC, and which surface contacts the ribosome versus the catalytic NAA30 subunit? - question: Is the EGAP-associated smooth-muscle/vascular phenotype a direct consequence of altered NatC substrate acetylation, or an EGAP-specific moonlighting role? suggested_experiments: - description: Reconstitute NatC in vitro with and without NAA35 to test whether the auxiliary subunit is required for catalytic activity and substrate selectivity of NAA30. - description: Cryo-EM of the NatC-ribosome complex to map the NAA35 scaffold contacts with the ribosome and the catalytic subunit. - description: N-terminomics of NAA35-depleted human cells to define the NatC-dependent N-terminal acetylome and test whether loss of the auxiliary subunit phenocopies loss of the catalytic subunit.