HYPK (Huntingtin-interacting protein K) is a small, largely intrinsically disordered protein that functions as a ribosome-associated, NatA-associated chaperone. It is a stable component of the N-terminal acetyltransferase A (NatA)/HYPK complex (with the catalytic NAA10 and auxiliary NAA15 subunits), where it binds principally to NAA15 and acts as a negative regulator that reduces the N-terminal acetyltransferase activity of NatA and modulates its interaction with NAA50 (the NatE catalytic subunit). Independently of catalysis, HYPK has chaperone-like activity: it suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine (polyQ) aggregation of an expanded N-terminal huntingtin (HTT) fragment in neuronal cells, an activity it exerts in association with the NatA complex. Through these chaperone and complex-modulating roles HYPK contributes to protein stabilization and is reported to negatively regulate apoptosis. HYPK is found in both the cytoplasm and the nucleus.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043066 negative regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference that HYPK negatively regulates apoptosis, a process downstream of its chaperone/anti-aggregation activity. Reason: Documented experimentally and by family inference but a downstream consequence of HYPK's chaperone role rather than its core molecular function. Supporting Evidence: PMID:17947297 plays an effective role in protecting neuronal cells against apoptosis induced by mutated N-terminal Htt by modulating the aggregate formation. |
| GO:0050821 protein stabilization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference that HYPK stabilizes proteins, consistent with its anti-aggregation chaperone activity. Reason: A plausible biological-process outcome of HYPK's chaperone function; retained as non-core relative to the chaperone MF. Supporting Evidence: PMID:17947297 In vitro and in vivo studies demonstrate that HYPK possesses a novel chaperone-like activity. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation of nuclear localization, consistent with the documented nuclear pool of HYPK. Reason: Nuclear pool documented; HYPK's core NatA-associated/chaperone role is cytoplasmic/ribosome-associated, so nuclear localization is non-core. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20154145} |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation of cytoplasmic localization, the principal site of HYPK's NatA-associated and chaperone activity. Reason: Cytoplasm is the main site of HYPK function; well supported. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Cytoplasm {ECO:0000269|PubMed:20154145}. Note=Within the NatA/HYPK complex, may localize to ribosomes. |
| GO:0006457 protein folding | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Inferred from the protein-folding-chaperone MF; HYPK participates in protein folding/quality control as a chaperone. Reason: A reasonable process annotation downstream of HYPK's chaperone MF; kept non-core. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells |
| GO:0005515 protein binding | IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu... | REMOVE | Summary: IntAct interaction with HTT (P42858, huntingtin), the namesake client of HYPK. Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: IntAct interaction with NAA15 (Q9BXJ9), HYPK's principal NatA-complex partner. Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Proteome-scale yeast two-hybrid interactome (e.g. P40222, P43355). Bare protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: IntAct interaction with NAA15 (Q9BXJ9). Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: High-throughput interactome capturing NAA15 (Q9BXJ9) and other partners. Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Neurodegeneration interactome capturing the HYPK-HTT (P42858) interaction. Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: BioPlex interactome capturing NAA15 (Q9BXJ9). Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Multimodal cell-maps interactome capturing NAA15 (Q9BXJ9). Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence nucleoplasmic localization, consistent with the documented nuclear pool of HYPK. Reason: Nuclear pool documented; non-core relative to cytoplasmic NatA-associated function. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20154145} |
| GO:0005634 nucleus | EXP PMID:20154145 The chaperone-like protein HYPK acts together with NatA in c... | KEEP AS NON CORE | Summary: Experimental nuclear localization of HYPK. Reason: Documented nuclear pool; non-core relative to cytoplasmic function. UniProt cites this study for the nuclear localization; the abstract does not describe it, so this defers to the curator's reading of the full text. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20154145} |
| GO:0005737 cytoplasm | EXP PMID:20154145 The chaperone-like protein HYPK acts together with NatA in c... | ACCEPT | Summary: Experimental cytoplasmic localization, the principal site of HYPK function. Reason: Core localization for HYPK's NatA-associated and chaperone roles. Supporting Evidence: PMID:20154145 HYPK, hNaa10p, and hNaa15p were associated with polysome fractions, indicating a function of HYPK associated with the NatA complex during protein translation. file:human/HYPK/HYPK-uniprot.txt Cytoplasm {ECO:0000269|PubMed:20154145}. Note=Within the NatA/HYPK complex, may localize to ribosomes. |
| GO:0044183 protein folding chaperone | EXP PMID:18076027 Huntingtin interacting protein HYPK is intrinsically unstruc... | ACCEPT | Summary: Experimental evidence (DisProt) that the intrinsically disordered HYPK acts as a chaperone preventing aggregation of clients; the core molecular function. Reason: Direct experimental evidence for HYPK's chaperone activity; this is its core, informative non-catalytic MF. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells |
| GO:0044183 protein folding chaperone | IDA PMID:18076027 Huntingtin interacting protein HYPK is intrinsically unstruc... | ACCEPT | Summary: Direct experimental evidence for HYPK chaperone activity; core MF. Reason: Direct experimental support for the core chaperone function. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells |
| GO:0005515 protein binding | IPI PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a... | REMOVE | Summary: IntAct interaction with HTT (P42858); the original HYPK-huntingtin interaction underpinning its anti-polyQ-aggregation activity. Generic protein binding term. Reason: Bare GO:0005515 protein binding carries no functional information, so under the generic protein-binding policy this row is REMOVE. Removal does not mean the reported interaction is false; the summary and any supporting text keep it on record. |
| GO:0005634 nucleus | IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a... | KEEP AS NON CORE | Summary: Direct nuclear localization of HYPK. Reason: Documented nuclear pool; non-core relative to cytoplasmic function. The abstract does not describe the imaging; this defers to the curator's reading of the full text of this cell-based HYPK study. Supporting Evidence: PMID:17947297 physically interacts with N-terminal Htt in Neuro2A cells and alters the numbers and distribution of aggregates formed by N-terminal Htt with 40Q. file:human/HYPK/HYPK-uniprot.txt SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:20154145} |
| GO:0005737 cytoplasm | IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a... | ACCEPT | Summary: Direct cytoplasmic localization of HYPK. Reason: Core localization for HYPK function. This defers to the curator's reading of the full text of this cell-based HYPK study. Supporting Evidence: PMID:17947297 physically interacts with N-terminal Htt in Neuro2A cells and alters the numbers and distribution of aggregates formed by N-terminal Htt with 40Q. file:human/HYPK/HYPK-uniprot.txt Cytoplasm {ECO:0000269|PubMed:20154145}. Note=Within the NatA/HYPK complex, may localize to ribosomes. |
| GO:0032991 protein-containing complex | IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a... | KEEP AS NON CORE | Summary: HYPK is part of a protein complex; this is captured more precisely by its membership in the NatA/HYPK complex. Reason: Generic complex term; HYPK's specific complex is the NatA/HYPK complex, so this high-level CC term is retained non-core. Recent cryo-EM-based synthesis places this HYPK-NatA assembly on translating ribosomes near the polypeptide exit tunnel together with NAC and the methionine aminopeptidases. Supporting Evidence: file:human/HYPK/HYPK-uniprot.txt Component of the N-terminal acetyltransferase A (NatA)/HYPK complex at least composed of NAA10, NAA15 and HYPK file:human/HYPK/HYPK-deep-research-falcon.md HYPK can be detected in ribosomal complexes that include NatA, the nascent polypeptide-associated complex (NAC), and methionine aminopeptidases (MAP1 or MAP2) |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a... | KEEP AS NON CORE | Summary: Direct evidence that HYPK negatively regulates apoptosis, downstream of its anti-aggregation chaperone activity. Reason: A documented downstream process; non-core relative to the chaperone MF. Supporting Evidence: PMID:17947297 Over-expression of this protein reduces poly Q-mediated caspase-2, caspase-3 and caspase-8 activations PMID:17947297 plays an effective role in protecting neuronal cells against apoptosis induced by mutated N-terminal Htt by modulating the aggregate formation. |
| GO:0050821 protein stabilization | IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a... | KEEP AS NON CORE | Summary: Direct evidence that HYPK stabilizes proteins (suppressing aggregation), a process outcome of its chaperone activity. Reason: Documented downstream process; non-core relative to the chaperone MF. The supporting data are the chaperone-like suppression of polyQ Htt aggregation. Supporting Evidence: PMID:17947297 In vitro and in vivo studies demonstrate that HYPK possesses a novel chaperone-like activity. |
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Download this section (compressed HTML)Q: Is HYPK's NatA-inhibitory activity a regulatory mechanism for global N-terminal acetylation, or primarily a means to couple NatA to nascent-chain chaperoning?
Q: Does HYPK's anti-polyQ-aggregation chaperone activity require its association with the NatA complex, or can free HYPK chaperone clients independently?
Q: Should HYPK be annotated as a selective autophagy receptor for polyneddylated cargo (NEDD8-binding UBA domain plus an atypical N-terminal LIR engaging LC3/GABARAP), as reported by Ghosh & Ranjan 2022 (PMID:34320889)? This HYPK-specific aggrephagy role is not yet reflected in the current GOA annotations and warrants expert curation of the primary full text.
Experiment: In vitro reconstitution measuring NatA N-terminal acetyltransferase activity with and without HYPK and NAA50 to quantify HYPK's inhibitory effect and its competition with NAA50.
Experiment: Aggregation assays (FRAP, filter-trap) of expanded-polyQ HTT in cells with HYPK knockout versus HYPK reconstituted in NatA-binding-deficient form to test whether chaperone activity requires NatA association.
Experiment: Selective ribosome profiling / N-terminal acetylome comparison upon HYPK depletion to define which nascent-chain substrates are co-regulated by HYPK and NatA.
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