HYPK

UniProt ID: Q9NX55
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

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.

Existing Annotations Review

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:
file:human/HYPK/HYPK-goa.tsv
GO:0043066 negative regulation of apoptotic process biological_process IDA PMID:17947297
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:
file:human/HYPK/HYPK-goa.tsv
GO:0050821 protein stabilization biological_process IDA PMID:17947297
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-goa.tsv
GO:0005634 nucleus cellular_component EXP PMID: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-goa.tsv
GO:0005737 cytoplasm cellular_component EXP PMID:20154145
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... 		KEEP AS NON CORE
Summary: IntAct interaction with HTT (P42858, huntingtin), the namesake client of HYPK. Generic protein binding term.
Reason: Records the functionally important HYPK-HTT interaction; informative function (chaperone) captured elsewhere.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:17500595 UniProtKB:P42858
GO:0005515 protein binding
IPI
PMID:24981860
Human-chromatin-related protein interactions identify a deme... 		KEEP AS NON CORE
Summary: IntAct interaction with NAA15 (Q9BXJ9), HYPK's principal NatA-complex partner. Generic protein binding term.
Reason: Records the central HYPK-NAA15 interaction underlying NatA/HYPK complex formation; informative function captured elsewhere.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:24981860 UniProtKB:Q9BXJ9
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		KEEP AS NON CORE
Summary: Proteome-scale yeast two-hybrid interactome (e.g. P40222, P43355). Bare protein binding term.
Reason: High-throughput interactome data; uninformative as a core MF.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:25416956 UniProtKB:P40222
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		KEEP AS NON CORE
Summary: IntAct interaction with NAA15 (Q9BXJ9). Generic protein binding term.
Reason: Records the central HYPK-NAA15 interaction; informative function captured elsewhere.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:28514442 UniProtKB:Q9BXJ9
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		KEEP AS NON CORE
Summary: High-throughput interactome capturing NAA15 (Q9BXJ9) and other partners. Generic protein binding term.
Reason: Records real interactions including HYPK-NAA15; generic MF kept non-core.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:32296183 UniProtKB:Q9BXJ9
GO:0005515 protein binding
IPI
PMID:32814053
Interactome Mapping Provides a Network of Neurodegenerative ... 		KEEP AS NON CORE
Summary: Neurodegeneration interactome capturing the HYPK-HTT (P42858) interaction. Generic protein binding term.
Reason: Records the HYPK-HTT interaction; informative function captured elsewhere.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:32814053 UniProtKB:P42858
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		KEEP AS NON CORE
Summary: BioPlex interactome capturing NAA15 (Q9BXJ9). Generic protein binding term.
Reason: Records the HYPK-NAA15 interaction; generic MF kept non-core.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:33961781 UniProtKB:Q9BXJ9
GO:0005515 protein binding
IPI
PMID:40205054
Multimodal cell maps as a foundation for structural and func... 		KEEP AS NON CORE
Summary: Multimodal cell-maps interactome capturing NAA15 (Q9BXJ9). Generic protein binding term.
Reason: Records the HYPK-NAA15 interaction; generic MF kept non-core.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:40205054 UniProtKB:Q9BXJ9
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-goa.tsv
GO:0005654 nucleoplasm cellular_component IDA GO_REF:0000052 HPA
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.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005634 nucleus cellular_component EXP PMID: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:
file:human/HYPK/HYPK-goa.tsv
GO:0005737 cytoplasm cellular_component EXP PMID:20154145
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... 		KEEP AS NON CORE
Summary: IntAct interaction with HTT (P42858); the original HYPK-huntingtin interaction underpinning its anti-polyQ-aggregation activity. Generic protein binding term.
Reason: Records the functionally central HYPK-HTT interaction; informative chaperone function captured elsewhere.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005515 protein binding molecular_function IPI PMID:17947297 UniProtKB:P42858
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.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005634 nucleus cellular_component IDA PMID:17947297
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.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0005737 cytoplasm cellular_component IDA PMID:17947297
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:
file:human/HYPK/HYPK-goa.tsv
GO:0043066 negative regulation of apoptotic process biological_process IDA PMID:17947297
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.
Supporting Evidence:
file:human/HYPK/HYPK-goa.tsv
GO:0050821 protein stabilization biological_process IDA PMID:17947297

Core Functions

Intrinsically disordered, ribosome/NatA-associated chaperone that suppresses aggregation of aggregation-prone clients, notably preventing polyglutamine aggregation of N-terminal huntingtin, acting in association with the NatA complex.

Molecular Function:
protein folding chaperone
Cellular Locations:
cytoplasm
Supporting Evidence:
  • file:human/HYPK/HYPK-uniprot.txt
    Has chaperone-like activity preventing polyglutamine (polyQ) aggregation of HTT in neuronal cells

Non-catalytic regulatory subunit of the NatA/HYPK N-terminal acetyltransferase complex that binds NAA15 and reduces (inhibits) the N-terminal acetyltransferase activity of the NAA10-NAA15 (NatA) complex and modulates its interaction with NAA50.

Molecular Function:
enzyme inhibitor activity
In Complex:
NatA complex
Supporting Evidence:
  • file:human/HYPK/HYPK-uniprot.txt
    Inhibits the N-terminal acetylation activity of the N-terminal acetyltransferase NAA10-NAA15 complex (also called the NatA complex)
  • file:human/HYPK/HYPK-deep-research-falcon.md
    HYPK inhibits the catalytic activity of NAA10 through an allosteric mechanism.
  • file:human/HYPK/HYPK-deep-research-falcon.md
    HYPK binding has a strong stabilizing effect on the NatA complex

References

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Suggested Questions for Experts

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.

Suggested Experiments

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.

Deep Research

Falcon

(HYPK-deep-research-falcon.md)

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📚 Additional Documentation

Notes

(HYPK-notes.md)

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Pn Notes

(HYPK-pn-notes.md)

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📄 View Raw YAML

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