DNAJC6

UniProt ID: O75061
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

DNAJC6 (auxilin, auxilin-1) is a neuronally enriched DnaJ/HSP40 co-chaperone that drives the HSC70/HSPA8-dependent uncoating of clathrin-coated vesicles. It is a multidomain protein comprising an N-terminal PTEN-like tensin-type phosphatase domain and a C2 domain (a phosphoinositide-binding membrane-targeting module that is thought to be catalytically degenerate), a long disordered clathrin-binding region, and a C-terminal J domain. Auxilin binds clathrin cages stoichiometrically (one per triskelion) and, through its J domain, recruits HSPA8/HSC70 and stimulates its ATPase activity to dismantle the clathrin lattice, thereby promoting clathrin-mediated endocytosis and the recycling/uncoating of synaptic vesicles at nerve terminals. Loss-of-function mutations cause autosomal-recessive juvenile- and early-onset Parkinson disease (PARK19A/PARK19B) through impaired synaptic vesicle endocytosis in dopaminergic neurons.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0030276 clathrin binding
IBA
GO_REF:0000033 		ACCEPT
Summary: Auxilin binds clathrin cages stoichiometrically, the recognition step that targets HSC70 to clathrin-coated vesicles. A core molecular function.
Reason: Direct clathrin binding by auxilin is well established (binds clathrin cages at one auxilin per triskelion) and is essential for its uncoating role.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
binds tightly to the clathrin cages, at a
GO:0031982 vesicle
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Auxilin acts on clathrin-coated vesicles; vesicle is a correct but generic compartment.
Reason: Correct but generic; the specific functional compartment is the clathrin-coated vesicle.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
clathrin-coated vesicle
GO:0014069 postsynaptic density
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference of postsynaptic density localization. Auxilin's best-established functional site is presynaptic endocytosis of synaptic vesicles.
Reason: A plausible neuronal localization by family inference, but auxilin's characterized role is in presynaptic clathrin-mediated synaptic vesicle endocytosis rather than the postsynaptic density; retained as non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
postsynaptic density
GO:0016191 synaptic vesicle uncoating
IBA
GO_REF:0000033 		ACCEPT
Summary: Auxilin mediates HSC70-dependent uncoating of clathrin from synaptic vesicles, a core biological process.
Reason: Strongly supported by auxilin's role as the cofactor for HSC70-mediated clathrin uncoating and by the synaptic phenotype of auxilin-knockout mice.
Supporting Evidence:
PMID:20160091
act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles
GO:0030136 clathrin-coated vesicle
IEA
GO_REF:0000044 		ACCEPT
Summary: Clathrin-coated vesicle localization, the core functional compartment where auxilin recruits HSC70 to drive uncoating.
Reason: Auxilin appears on coated vesicles in transient bursts after vesicle release; this is its principal site of action.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasmic vesicle, clathrin-coated vesicle
GO:1905443 regulation of clathrin coat assembly
IEA
GO_REF:0000117 		ACCEPT
Summary: Auxilin regulates clathrin coat assembly/disassembly; its depletion causes accumulation of nonproductive clathrin cages.
Reason: Supported experimentally by IMP evidence (PMID:18489706) showing auxilin depletion alters clathrin coat formation.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
prevent the formation of nonproductive clathrin cages
GO:0014069 postsynaptic density
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ensembl-projected postsynaptic density localization from the mouse ortholog.
Reason: As for the IBA postsynaptic density annotation, plausible but not auxilin's core presynaptic functional site.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
postsynaptic density
GO:0016191 synaptic vesicle uncoating
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl-projected synaptic vesicle uncoating, redundant with the IBA and ISS annotations of the same process.
Reason: Core auxilin process; redundant with stronger evidence for the same term.
Supporting Evidence:
PMID:20160091
act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles
GO:0036465 synaptic vesicle recycling
IEA
GO_REF:0000107 		ACCEPT
Summary: Auxilin participates in synaptic vesicle recycling by uncoating clathrin during endocytic retrieval, projected from the mouse ortholog.
Reason: Supported by the synaptic phenotype of auxilin-knockout mice showing impaired clathrin-mediated synaptic vesicle endocytosis and recycling.
Supporting Evidence:
PMID:20160091
the specialized role of auxilin in the recycling of synaptic vesicles at synapses
GO:0045202 synapse
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Synapse localization projected from the mouse ortholog; auxilin acts at presynaptic endocytic zones.
Reason: Correct neuronal compartment but generic; the more specific site is the presynaptic endocytic zone / clathrin-coated vesicle.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
synaptic vesicles
GO:0072583 clathrin-dependent endocytosis
IEA
GO_REF:0000120 		ACCEPT
Summary: Auxilin participates in clathrin-mediated/clathrin-dependent endocytosis, here from automated annotation; corroborated by direct IMP evidence.
Reason: Core auxilin process, directly demonstrated by RNAi (PMID:18489706); redundant with the IMP annotation.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
participates in clathrin-mediated endocytosis of synaptic vesicles
GO:0098894 extrinsic component of presynaptic endocytic zone membrane
IEA
GO_REF:0000107 		ACCEPT
Summary: Localization to the presynaptic endocytic zone membrane (extrinsic component), projected from the mouse ortholog; matches auxilin's role in synaptic vesicle endocytosis.
Reason: A specific and accurate functional localization for auxilin, where it acts on clathrin-coated pits/vesicles at the presynaptic endocytic zone.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
clathrin-mediated endocytosis of synaptic vesicles
GO:0072583 clathrin-dependent endocytosis
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS clathrin-dependent endocytosis from the Drosophila ortholog, redundant with the IMP and IEA annotations.
Reason: Core process; redundant with directly demonstrated evidence.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
participates in clathrin-mediated endocytosis of synaptic vesicles
GO:0005515 protein binding
IPI
PMID:29735704
LRRK2 phosphorylation of auxilin mediates synaptic defects i... 		MODIFY
Summary: IPI capture of the auxilin-CLTC (clathrin heavy chain, Q00610) interaction. The bare protein binding term is uninformative; this interaction reflects auxilin's clathrin heavy chain binding.
Reason: Per curation guidelines bare protein binding is uninformative. The WITH partner is CLTC (clathrin heavy chain, Q00610), so the specific molecular function is clathrin heavy chain binding.
Proposed replacements: clathrin heavy chain binding
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
Interacts with CLTC
GO:0031072 heat shock protein binding
ISS
GO_REF:0000024 		ACCEPT
Summary: Auxilin binds the heat shock protein HSPA8/HSC70 in an ATP-dependent manner and stimulates its ATPase activity; this HSP70 co-chaperone function is core.
Reason: The J-domain-mediated interaction with HSPA8/HSC70 is central to auxilin's uncoating mechanism and is well documented.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
Interacts with HSPA8/HSC70 in an ATP-dependent manner; this interaction stimulates the HSPA8's ATPase activity
GO:0032050 clathrin heavy chain binding
ISS
GO_REF:0000024 		ACCEPT
Summary: Auxilin binds the clathrin heavy chain (CLTC), producing local changes in heavy-chain contacts; a core molecular function.
Reason: Directly supported by the auxilin-CLTC interaction (also captured by IPI) that distorts the clathrin coat to enable disassembly.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
Interacts with CLTC; this interaction produces a local change in heavy-chain contacts
GO:0072318 clathrin coat disassembly
ISS
GO_REF:0000024 		ACCEPT
Summary: Auxilin drives disassembly of the clathrin coat by recruiting HSPA8 and triggering ATP-hydrolysis-driven dismantling of the cage; a core process.
Reason: Central mechanism of auxilin; the J domain is required for basket dissociation.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
concerted dismantling of the cage into component triskelia
GO:0072583 clathrin-dependent endocytosis
IMP
PMID:18489706
Auxilin depletion causes self-assembly of clathrin into memb... 		ACCEPT
Summary: RNAi depletion of auxilins inhibits clathrin-mediated endocytosis, providing direct experimental evidence for auxilin's role.
Reason: Directly demonstrated by mutant-phenotype evidence; a core auxilin process.
Supporting Evidence:
PMID:18489706
both auxilins need to be depleted for inhibition of clathrin-mediated endocytosis
GO:1905443 regulation of clathrin coat assembly
IMP
PMID:18489706
Auxilin depletion causes self-assembly of clathrin into memb... 		ACCEPT
Summary: Auxilin depletion causes accumulation of nonproductive clathrin cages, showing auxilin regulates clathrin coat assembly/turnover.
Reason: Directly supported by the depletion phenotype (self-assembly of clathrin into membraneless cages).
Supporting Evidence:
PMID:18489706
prevent the formation of nonproductive clathrin cages in the cytosol
GO:0030136 clathrin-coated vesicle
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS clathrin-coated vesicle localization, redundant with the IEA annotation.
Reason: Core functional compartment; redundant with stronger evidence.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasmic vesicle, clathrin-coated vesicle
GO:0030276 clathrin binding
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS clathrin binding from the Drosophila ortholog, redundant with the IBA annotation.
Reason: Core molecular function; redundant with the IBA clathrin binding annotation.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-uniprot.txt
binds tightly to the clathrin cages, at a
GO:0036465 synaptic vesicle recycling
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS synaptic vesicle recycling from the mouse ortholog, redundant with the IEA annotation.
Reason: Core auxilin process; redundant with the knockout-supported annotation.
Supporting Evidence:
PMID:20160091
the specialized role of auxilin in the recycling of synaptic vesicles at synapses
GO:0016191 synaptic vesicle uncoating
ISS
PMID:20160091
Endocytosis and clathrin-uncoating defects at synapses of au... 		ACCEPT
Summary: ISS synaptic vesicle uncoating based on the auxilin-knockout mouse, demonstrating auxilin's specialized synaptic uncoating role.
Reason: Strongly supported by the knockout phenotype showing endocytosis and clathrin-uncoating defects at synapses.
Supporting Evidence:
PMID:20160091
Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice
GO:0005829 cytosol
TAS
Reactome:R-HSA-421836 		KEEP AS NON CORE
Summary: Reactome cytosol localization for auxilin (clathrin-mediated endocytosis pathway); auxilin cycles between a soluble cytosolic pool and clathrin coats.
Reason: Auxilin has a genuine cytosolic pool from which it is recruited to coated vesicles, but the cytosol localization is less informative than its clathrin-coated-vesicle site of action; one of several redundant Reactome cytosol annotations.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-432688 		KEEP AS NON CORE
Summary: Redundant Reactome cytosol localization (vesicle biogenesis pathway).
Reason: Redundant cytosol annotation; genuine but non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868658 		KEEP AS NON CORE
Summary: Redundant Reactome cytosol localization.
Reason: Redundant cytosol annotation; genuine but non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868659 		KEEP AS NON CORE
Summary: Redundant Reactome cytosol localization.
Reason: Redundant cytosol annotation; genuine but non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-8868660 		KEEP AS NON CORE
Summary: Redundant Reactome cytosol localization.
Reason: Redundant cytosol annotation; genuine but non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-8869438 		KEEP AS NON CORE
Summary: Redundant Reactome cytosol localization.
Reason: Redundant cytosol annotation; genuine but non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-8871193 		KEEP AS NON CORE
Summary: Redundant Reactome cytosol localization.
Reason: Redundant cytosol annotation; genuine but non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol
GO:0005829 cytosol
TAS
Reactome:R-HSA-8871194 		KEEP AS NON CORE
Summary: Redundant Reactome cytosol localization.
Reason: Redundant cytosol annotation; genuine but non-core.
Supporting Evidence:
file:human/DNAJC6/DNAJC6-goa.tsv
cytosol

Core Functions

Clathrin-uncoating co-chaperone that binds the clathrin heavy chain and clathrin cages and, via its J domain, recruits HSPA8/HSC70 and stimulates its ATPase activity to drive ATP-dependent disassembly of the clathrin coat.

Molecular Function:
clathrin heavy chain binding
Cellular Locations:
clathrin-coated vesicle
Supporting Evidence:
  • file:human/DNAJC6/DNAJC6-uniprot.txt
    Interacts with CLTC; this interaction produces a local change in heavy-chain contacts
  • file:human/DNAJC6/DNAJC6-uniprot.txt
    binds tightly to the clathrin cages, at a

HSP70/HSC70 co-chaperone activity, recruiting and stimulating the ATPase of HSPA8/HSC70 through its J domain to power clathrin coat disassembly.

Molecular Function:
heat shock protein binding
Cellular Locations:
clathrin-coated vesicle
Supporting Evidence:
  • file:human/DNAJC6/DNAJC6-uniprot.txt
    Interacts with HSPA8/HSC70 in an ATP-dependent manner; this interaction stimulates the HSPA8's ATPase activity

Drives clathrin coat disassembly / synaptic vesicle uncoating during clathrin-mediated endocytosis, supporting synaptic vesicle recycling at nerve terminals.

Molecular Function:
heat shock protein binding
Directly Involved In:
clathrin coat disassembly
Cellular Locations:
extrinsic component of presynaptic endocytic zone membrane
Supporting Evidence:
  • PMID:20160091
    act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles

References

GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:18489706
Auxilin depletion causes self-assembly of clathrin into membraneless cages in vivo.
  • Auxilin is a cofactor for HSC70-mediated uncoating of clathrin-coated vesicles; depletion of both auxilin isoforms inhibits clathrin-mediated endocytosis and causes formation of nonproductive membraneless clathrin cages.
PMID:20160091
Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice.
  • Auxilin and GAK act as co-chaperones supporting HSC70-dependent clathrin uncoating of clathrin-coated vesicles; auxilin-knockout synapses show increased clathrin-coated vesicles/empty cages and impaired synaptic vesicle endocytosis.
PMID:29735704
LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson's disease.
  • LRRK2 phosphorylates auxilin in its clathrin-binding domain, altering clathrin binding and disrupting synaptic vesicle endocytosis in PD dopaminergic neurons; auxilin interacts with the clathrin heavy chain CLTC.
Reactome:R-HSA-421836
Clathrin-mediated endocytosis (cytosol localization)
Reactome:R-HSA-432688
Vesicle biogenesis (cytosol localization)
Reactome:R-HSA-8868658
Clathrin-mediated endocytosis (cytosol localization)
Reactome:R-HSA-8868659
Clathrin-mediated endocytosis (cytosol localization)
Reactome:R-HSA-8868660
Clathrin-mediated endocytosis (cytosol localization)
Reactome:R-HSA-8869438
Clathrin-mediated endocytosis (cytosol localization)
Reactome:R-HSA-8871193
Clathrin-mediated endocytosis (cytosol localization)
Reactome:R-HSA-8871194
Clathrin-mediated endocytosis (cytosol localization)
file:human/DNAJC6/DNAJC6-uniprot.txt
UniProt entry O75061 (AUXI_HUMAN), auxilin
  • Auxilin recruits HSPA8/HSC70 to clathrin-coated vesicles and promotes the ATP-dependent dissociation of clathrin from CCVs; binds clathrin cages stoichiometrically; the J domain mediates HSPA8 interaction and is required for basket dissociation; mutations cause PARK19A/PARK19B Parkinson disease.

Suggested Questions for Experts

Q: Is the PTEN-like phosphatase domain of auxilin catalytically active, or does it function purely as a phosphoinositide-binding membrane-targeting module that times auxilin recruitment to coated vesicles?

Q: How does LRRK2-mediated phosphorylation of auxilin's clathrin-binding domain mechanistically convert into the synaptic vesicle endocytosis defects seen in Parkinson disease dopaminergic neurons?

Q: To what extent can the ubiquitous homolog GAK compensate for neuronal auxilin loss, and does incomplete compensation explain the dopaminergic-neuron vulnerability in PARK19?

Suggested Experiments

Experiment: Reconstituted clathrin-cage disassembly assays with purified auxilin (wild-type, J-domain HPD mutant, and PARK19 disease variants) plus HSPA8 and ATP to quantify uncoating activity and HSPA8 ATPase stimulation.

Experiment: Phosphatase activity assays on the auxilin PTEN-like domain against phosphoprotein and phosphoinositide substrates, with active-site (Cys164) mutants, to resolve whether it is a bona fide phosphatase or a degenerate lipid-binding domain.

Experiment: Live-cell imaging of clathrin and HSC70 dynamics in DNAJC6-knockout versus rescued neurons (wild-type vs PARK19 variants) to map the uncoating defect and test GAK compensation.

📚 Additional Documentation

Notes

(DNAJC6-notes.md)

DNAJC6 (O75061) research notes

Identity

  • Auxilin (auxilin-1); DnaJ homolog subfamily C member 6. 913 aa.
  • Domains: N-terminal tensin-type phosphatase (PTEN-like) domain (aa 55-222) + C2 tensin-type domain (228-366) [PTEN/C2 module]; long disordered clathrin-binding middle region; C-terminal J domain (aa 849-913) [file:human/DNAJC6/DNAJC6-uniprot.txt "DOMAIN 849..913 /note=\"J\""].
  • Neuronal-specific (brain/retina enriched); cyclin-G-associated kinase GAK is the ubiquitous homolog.

Function (UniProt FUNCTION + PMID:18489706, 20160091)

  • Co-chaperone that recruits HSPA8/HSC70 to clathrin-coated vesicles (CCVs) and promotes the ATP-dependent dissociation of clathrin from CCVs; participates in clathrin-mediated endocytosis of synaptic vesicles and recycling [uniprot FUNCTION].
  • Binds tightly to clathrin cages (1 auxilin per triskelion); HSPA8:ATP then binds, ATP hydrolysis dismantles the cage. J domain mediates HSPA8 interaction and is required for basket dissociation [uniprot DOMAIN].
  • PMID:18489706 (Hirst et al.): "Auxilin is a cofactor for Hsc70-mediated uncoating of clathrin-coated vesicles (CCVs)"; depletion of both auxilins inhibits clathrin-mediated endocytosis and causes nonproductive clathrin cages.
  • PMID:20160091 (Yim et al.): auxilin KO mouse; "auxilin and ... GAK ... act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles"; specialized role in synaptic vesicle recycling.

Phosphatase

  • Annotated EC 3.1.3.- "May act as a protein phosphatase and/or a lipid phosphatase." The PTEN-like phosphatase domain is generally considered catalytically inactive/degenerate in auxilin (acts as a phosphoinositide-binding targeting module). Keep phosphatase MF cautiously / non-core; it is speculative ("May act").

Interactions

  • HSPA8/HSC70 (ATP-dependent; stimulates ATPase); CLTC (clathrin heavy chain, Q00610; IPI PMID:29735704); AP2A2; DNM1(GTP).
  • PMID:29735704 (Nguyen & Krainc): LRRK2 phosphorylates auxilin at Ser-loc in clathrin-binding domain -> disrupted SVE in PD dopaminergic neurons. (Note: paper text says Ser627; UniProt residue Ser-570 in canonical numbering. The IPI is CLTC.)

Disease

  • PARK19A (juvenile-onset, autosomal recessive) and PARK19B (early-onset) Parkinson disease [PMID:22563501, 23211418, 26703368, 26528954]. Loss-of-function -> impaired synaptic vesicle endocytosis in dopaminergic neurons.

Curation judgment

  • Core MF: (1) clathrin binding / clathrin heavy chain binding (GO:0030276 / GO:0032050) — direct, ISS-supported and IPI with CLTC; (2) HSP70/HSC70 co-chaperone (heat shock protein binding GO:0031072 / ATPase activator) — J domain recruits & stimulates HSPA8.
  • Core BP: clathrin coat disassembly / synaptic vesicle uncoating / clathrin-dependent endocytosis (IMP for human; ISS/IBA for the rest). ACCEPT the IMP and IBA; ISS duplicates ACCEPT/KEEP_AS_NON_CORE.
  • Cytosol (many redundant Reactome TAS) and CCV / vesicle / postsynaptic density localizations: ACCEPT (clathrin-coated vesicle, cytoplasm) or KEEP_AS_NON_CORE.
  • protein binding IPI (CLTC, Q00610): MODIFY to clathrin heavy chain binding (GO:0032050) — informative MF.
  • phosphoprotein phosphatase activity (IEA-KW): speculative degenerate phosphatase; MARK_AS_OVER_ANNOTATED / KEEP_AS_NON_CORE.

Pn Notes

(DNAJC6-pn-notes.md)

DNAJC6 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O75061
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-07b
  • Batch change status: added

Source Files Checked

Deep Research Files

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

AIGR Review Snapshot

  • Description: DNAJC6 (auxilin, auxilin-1) is a neuronally enriched DnaJ/HSP40 co-chaperone that drives the HSC70/HSPA8-dependent uncoating of clathrin-coated vesicles. It is a multidomain protein comprising an N-terminal PTEN-like tensin-type phosphatase domain and a C2 domain (a phosphoinositide-binding membrane-targeting module that is thought to be catalytically degenerate), a long disordered clathrin-binding region, and a C-terminal J domain. Auxilin binds clathrin cages stoichiometrically (one per triskelion) and, through its J domain, recruits HSPA8/HSC70 and stimulates its ATPase activity to dismantle the clathrin lattice, thereby promoting clathrin-mediated endocytosis and the recycling/uncoating of synaptic vesicles at nerve terminals. Loss-of-function mutations cause autosomal-recessive juvenile- and early-onset Parkinson disease (PARK19A/PARK19B) through impaired synaptic vesicle endocytosis in dopaminergic neurons.
  • Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 12; MODIFY: 1

PN Consistency Summary

  • Consistency: Consistent, with one MF-specificity nuance. Deep research (notes), review and PN converge on DNAJC6/auxilin as the neuronal clathrin-uncoating co-chaperone: binds clathrin cages (1 per triskelion) and, via its C-terminal J domain, recruits HSPA8/HSC70 and stimulates its ATPase to dismantle the coat; PARK19 disease gene (PMID:18489706 VERIFIED, 20160091 VERIFIED, 29735704). The review's chaperone-binding core MF is GO:0031072 heat shock protein binding (ISS, ACCEPT) plus clathrin binding/clathrin heavy chain binding (GO:0030276/GO:0032050). PN projects the narrower GO:0030544 Hsp70 protein binding — and since auxilin binds specifically HSPA8/HSC70 (an Hsp70), GO:0030544 is in fact MORE accurate than the review's GO:0031072; GOA currently has only GO:0031072. (GO:0030544 is_a GO:0031072.)
  • PN story / NEW pressure: GO:0030544 (verified real) is not yet in GOA or the review (which uses the parent GO:0031072). This is a legitimate ADD / refinement: auxilin's documented partner is HSPA8/HSC70, so the specific Hsp70 protein binding term is defensible and more informative. goa_status=more_specific_than_existing_goa is exactly right.
  • Evidence alignment: PN carries no row references. Review/notes cite the verified uncoating literature (PMID:18489706, 20160091) + CLTC/LRRK2 (PMID:29735704). Strong, no divergence from PN.
  • Verdict: Consistent and well-supported; PN's GO:0030544 is a defensible more-specific ADD over the review/GOA's GO:0031072. Recommended edits: [YAML][MAP] consider replacing/supplementing GO:0031072 heat shock protein binding with the more specific GO:0030544 Hsp70 protein binding in the review core MF (auxilin's documented partner is HSPA8/HSC70), aligning with the PN projection.

Full Consistency Review

  • UniProt: O75061 · batch: proteostasis-batch-2026-06-07b · review status: COMPLETE
  • PN placement: Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone (branch CY) ; PN-node mapping: type → mapped/ok_for_propagation_to_go GO:0030544 Hsp70 protein binding (goa_status=more_specific_than_existing_goa); all ancestor nodes no_mapping.
  • Consistency: Consistent, with one MF-specificity nuance. Deep research (notes), review and PN converge on DNAJC6/auxilin as the neuronal clathrin-uncoating co-chaperone: binds clathrin cages (1 per triskelion) and, via its C-terminal J domain, recruits HSPA8/HSC70 and stimulates its ATPase to dismantle the coat; PARK19 disease gene (PMID:18489706 VERIFIED, 20160091 VERIFIED, 29735704). The review's chaperone-binding core MF is GO:0031072 heat shock protein binding (ISS, ACCEPT) plus clathrin binding/clathrin heavy chain binding (GO:0030276/GO:0032050). PN projects the narrower GO:0030544 Hsp70 protein binding — and since auxilin binds specifically HSPA8/HSC70 (an Hsp70), GO:0030544 is in fact MORE accurate than the review's GO:0031072; GOA currently has only GO:0031072. (GO:0030544 is_a GO:0031072.)
  • PN story / NEW pressure: GO:0030544 (verified real) is not yet in GOA or the review (which uses the parent GO:0031072). This is a legitimate ADD / refinement: auxilin's documented partner is HSPA8/HSC70, so the specific Hsp70 protein binding term is defensible and more informative. goa_status=more_specific_than_existing_goa is exactly right.
  • Mapping strategy: No change to node breadth. Unlike rejected broad cases (TOMM20/HSPA8/RAB7A), here the PN projection is narrower and more specific than existing GOA/review and is well-supported — a genuine refinement, not an over-reach.
  • Evidence alignment: PN carries no row references. Review/notes cite the verified uncoating literature (PMID:18489706, 20160091) + CLTC/LRRK2 (PMID:29735704). Strong, no divergence from PN.
  • Verdict: Consistent and well-supported; PN's GO:0030544 is a defensible more-specific ADD over the review/GOA's GO:0031072. Recommended edits: [YAML][MAP] consider replacing/supplementing GO:0031072 heat shock protein binding with the more specific GO:0030544 Hsp70 protein binding in the review core MF (auxilin's documented partner is HSPA8/HSC70), aligning with the PN projection.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-07b
  • review_yaml: genes/human/DNAJC6/DNAJC6-ai-review.yaml
  • PN workbook rows: 1

PN row 1: Cytonuclear proteostasis | Chaperone | HSP70 system | J-domain containing HSP70 cochaperone

  • UniProt: O75061
  • In branches: CY
  • PN-node mapping records (path + ancestors):
    • [type] Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0030544 Hsp70 protein binding]
      rationale: In the PN hierarchy, this type denotes J-domain cochaperones assigned to the HSP70 system. Their shared mechanistic role is direct interaction with HSP70-family chaperones, making Hsp70 protein binding the most defensible GO target in the current cache.
    • [group] Cytonuclear proteostasis|Chaperone|HSP70 system
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [class] Cytonuclear proteostasis|Chaperone
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a specific GO class. The member genes span multiple activities, complexes, or contexts, so propagation from this node would overstate the shared biology; use narrower child or gene-level curations.
    • [branch] Cytonuclear proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

Projected GO annotations (1)

  • GO:0030544 Hsp70 protein binding | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Cytonuclear proteostasis|Chaperone|HSP70 system|J-domain containing HSP70 cochaperone

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.

📄 View Raw YAML

 
id: O75061
gene_symbol: DNAJC6
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: DNAJC6 (auxilin, auxilin-1) is a neuronally enriched DnaJ/HSP40 co-chaperone that drives the HSC70/HSPA8-dependent uncoating of clathrin-coated vesicles. It is a multidomain protein comprising an N-terminal PTEN-like tensin-type phosphatase domain and a C2 domain (a phosphoinositide-binding membrane-targeting module that is thought to be catalytically degenerate), a long disordered clathrin-binding region, and a C-terminal J domain. Auxilin binds clathrin cages stoichiometrically (one per triskelion) and, through its J domain, recruits HSPA8/HSC70 and stimulates its ATPase activity to dismantle the clathrin lattice, thereby promoting clathrin-mediated endocytosis and the recycling/uncoating of synaptic vesicles at nerve terminals. Loss-of-function mutations cause autosomal-recessive juvenile- and early-onset Parkinson disease (PARK19A/PARK19B) through impaired synaptic vesicle endocytosis in dopaminergic neurons.
alternative_products:
- name: '1'
  id: O75061-1
- name: '2'
  id: O75061-2
  sequence_note: VSP_019580
- name: '3'
  id: O75061-3
  sequence_note: VSP_019579, VSP_019581
- name: '4'
  id: O75061-4
  sequence_note: VSP_019579
existing_annotations:
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Auxilin binds clathrin cages stoichiometrically, the recognition step that targets HSC70 to clathrin-coated vesicles. A core molecular function.
    action: ACCEPT
    reason: Direct clathrin binding by auxilin is well established (binds clathrin cages at one auxilin per triskelion) and is essential for its uncoating role.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: binds tightly to the clathrin cages, at a
- term:
    id: GO:0031982
    label: vesicle
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Auxilin acts on clathrin-coated vesicles; vesicle is a correct but generic compartment.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific functional compartment is the clathrin-coated vesicle.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: clathrin-coated vesicle
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of postsynaptic density localization. Auxilin's best-established functional site is presynaptic endocytosis of synaptic vesicles.
    action: KEEP_AS_NON_CORE
    reason: A plausible neuronal localization by family inference, but auxilin's characterized role is in presynaptic clathrin-mediated synaptic vesicle endocytosis rather than the postsynaptic density; retained as non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: postsynaptic density
- term:
    id: GO:0016191
    label: synaptic vesicle uncoating
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Auxilin mediates HSC70-dependent uncoating of clathrin from synaptic vesicles, a core biological process.
    action: ACCEPT
    reason: Strongly supported by auxilin's role as the cofactor for HSC70-mediated clathrin uncoating and by the synaptic phenotype of auxilin-knockout mice.
    supported_by:
    - reference_id: PMID:20160091
      supporting_text: act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Clathrin-coated vesicle localization, the core functional compartment where auxilin recruits HSC70 to drive uncoating.
    action: ACCEPT
    reason: Auxilin appears on coated vesicles in transient bursts after vesicle release; this is its principal site of action.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasmic vesicle, clathrin-coated vesicle'
- term:
    id: GO:1905443
    label: regulation of clathrin coat assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Auxilin regulates clathrin coat assembly/disassembly; its depletion causes accumulation of nonproductive clathrin cages.
    action: ACCEPT
    reason: Supported experimentally by IMP evidence (PMID:18489706) showing auxilin depletion alters clathrin coat formation.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: prevent the formation of nonproductive clathrin cages
- term:
    id: GO:0014069
    label: postsynaptic density
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-projected postsynaptic density localization from the mouse ortholog.
    action: KEEP_AS_NON_CORE
    reason: As for the IBA postsynaptic density annotation, plausible but not auxilin's core presynaptic functional site.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: postsynaptic density
- term:
    id: GO:0016191
    label: synaptic vesicle uncoating
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected synaptic vesicle uncoating, redundant with the IBA and ISS annotations of the same process.
    action: ACCEPT
    reason: Core auxilin process; redundant with stronger evidence for the same term.
    supported_by:
    - reference_id: PMID:20160091
      supporting_text: act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles
- term:
    id: GO:0036465
    label: synaptic vesicle recycling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Auxilin participates in synaptic vesicle recycling by uncoating clathrin during endocytic retrieval, projected from the mouse ortholog.
    action: ACCEPT
    reason: Supported by the synaptic phenotype of auxilin-knockout mice showing impaired clathrin-mediated synaptic vesicle endocytosis and recycling.
    supported_by:
    - reference_id: PMID:20160091
      supporting_text: the specialized role of auxilin in the recycling of synaptic vesicles at synapses
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Synapse localization projected from the mouse ortholog; auxilin acts at presynaptic endocytic zones.
    action: KEEP_AS_NON_CORE
    reason: Correct neuronal compartment but generic; the more specific site is the presynaptic endocytic zone / clathrin-coated vesicle.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: synaptic vesicles
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Auxilin participates in clathrin-mediated/clathrin-dependent endocytosis, here from automated annotation; corroborated by direct IMP evidence.
    action: ACCEPT
    reason: Core auxilin process, directly demonstrated by RNAi (PMID:18489706); redundant with the IMP annotation.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: participates in clathrin-mediated endocytosis of synaptic vesicles
- term:
    id: GO:0098894
    label: extrinsic component of presynaptic endocytic zone membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: Localization to the presynaptic endocytic zone membrane (extrinsic component), projected from the mouse ortholog; matches auxilin's role in synaptic vesicle endocytosis.
    action: ACCEPT
    reason: A specific and accurate functional localization for auxilin, where it acts on clathrin-coated pits/vesicles at the presynaptic endocytic zone.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: clathrin-mediated endocytosis of synaptic vesicles
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS clathrin-dependent endocytosis from the Drosophila ortholog, redundant with the IMP and IEA annotations.
    action: ACCEPT
    reason: Core process; redundant with directly demonstrated evidence.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: participates in clathrin-mediated endocytosis of synaptic vesicles
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29735704
  qualifier: enables
  review:
    summary: IPI capture of the auxilin-CLTC (clathrin heavy chain, Q00610) interaction. The bare protein binding term is uninformative; this interaction reflects auxilin's clathrin heavy chain binding.
    action: MODIFY
    reason: Per curation guidelines bare protein binding is uninformative. The WITH partner is CLTC (clathrin heavy chain, Q00610), so the specific molecular function is clathrin heavy chain binding.
    proposed_replacement_terms:
    - id: GO:0032050
      label: clathrin heavy chain binding
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: Interacts with CLTC
- term:
    id: GO:0031072
    label: heat shock protein binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Auxilin binds the heat shock protein HSPA8/HSC70 in an ATP-dependent manner and stimulates its ATPase activity; this HSP70 co-chaperone function is core.
    action: ACCEPT
    reason: The J-domain-mediated interaction with HSPA8/HSC70 is central to auxilin's uncoating mechanism and is well documented.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: Interacts with HSPA8/HSC70 in an ATP-dependent manner; this interaction stimulates the HSPA8's ATPase activity
- term:
    id: GO:0032050
    label: clathrin heavy chain binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Auxilin binds the clathrin heavy chain (CLTC), producing local changes in heavy-chain contacts; a core molecular function.
    action: ACCEPT
    reason: Directly supported by the auxilin-CLTC interaction (also captured by IPI) that distorts the clathrin coat to enable disassembly.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: Interacts with CLTC; this interaction produces a local change in heavy-chain contacts
- term:
    id: GO:0072318
    label: clathrin coat disassembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Auxilin drives disassembly of the clathrin coat by recruiting HSPA8 and triggering ATP-hydrolysis-driven dismantling of the cage; a core process.
    action: ACCEPT
    reason: Central mechanism of auxilin; the J domain is required for basket dissociation.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: concerted dismantling of the cage into component triskelia
- term:
    id: GO:0072583
    label: clathrin-dependent endocytosis
  evidence_type: IMP
  original_reference_id: PMID:18489706
  qualifier: involved_in
  review:
    summary: RNAi depletion of auxilins inhibits clathrin-mediated endocytosis, providing direct experimental evidence for auxilin's role.
    action: ACCEPT
    reason: Directly demonstrated by mutant-phenotype evidence; a core auxilin process.
    supported_by:
    - reference_id: PMID:18489706
      supporting_text: both auxilins need to be depleted for inhibition of clathrin-mediated endocytosis
- term:
    id: GO:1905443
    label: regulation of clathrin coat assembly
  evidence_type: IMP
  original_reference_id: PMID:18489706
  qualifier: involved_in
  review:
    summary: Auxilin depletion causes accumulation of nonproductive clathrin cages, showing auxilin regulates clathrin coat assembly/turnover.
    action: ACCEPT
    reason: Directly supported by the depletion phenotype (self-assembly of clathrin into membraneless cages).
    supported_by:
    - reference_id: PMID:18489706
      supporting_text: prevent the formation of nonproductive clathrin cages in the cytosol
- term:
    id: GO:0030136
    label: clathrin-coated vesicle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS clathrin-coated vesicle localization, redundant with the IEA annotation.
    action: ACCEPT
    reason: Core functional compartment; redundant with stronger evidence.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasmic vesicle, clathrin-coated vesicle'
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ISS clathrin binding from the Drosophila ortholog, redundant with the IBA annotation.
    action: ACCEPT
    reason: Core molecular function; redundant with the IBA clathrin binding annotation.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
      supporting_text: binds tightly to the clathrin cages, at a
- term:
    id: GO:0036465
    label: synaptic vesicle recycling
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS synaptic vesicle recycling from the mouse ortholog, redundant with the IEA annotation.
    action: ACCEPT
    reason: Core auxilin process; redundant with the knockout-supported annotation.
    supported_by:
    - reference_id: PMID:20160091
      supporting_text: the specialized role of auxilin in the recycling of synaptic vesicles at synapses
- term:
    id: GO:0016191
    label: synaptic vesicle uncoating
  evidence_type: ISS
  original_reference_id: PMID:20160091
  qualifier: involved_in
  review:
    summary: ISS synaptic vesicle uncoating based on the auxilin-knockout mouse, demonstrating auxilin's specialized synaptic uncoating role.
    action: ACCEPT
    reason: Strongly supported by the knockout phenotype showing endocytosis and clathrin-uncoating defects at synapses.
    supported_by:
    - reference_id: PMID:20160091
      supporting_text: Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-421836
  qualifier: located_in
  review:
    summary: Reactome cytosol localization for auxilin (clathrin-mediated endocytosis pathway); auxilin cycles between a soluble cytosolic pool and clathrin coats.
    action: KEEP_AS_NON_CORE
    reason: Auxilin has a genuine cytosolic pool from which it is recruited to coated vesicles, but the cytosol localization is less informative than its clathrin-coated-vesicle site of action; one of several redundant Reactome cytosol annotations.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-432688
  qualifier: located_in
  review:
    summary: Redundant Reactome cytosol localization (vesicle biogenesis pathway).
    action: KEEP_AS_NON_CORE
    reason: Redundant cytosol annotation; genuine but non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868658
  qualifier: located_in
  review:
    summary: Redundant Reactome cytosol localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant cytosol annotation; genuine but non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868659
  qualifier: located_in
  review:
    summary: Redundant Reactome cytosol localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant cytosol annotation; genuine but non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8868660
  qualifier: located_in
  review:
    summary: Redundant Reactome cytosol localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant cytosol annotation; genuine but non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8869438
  qualifier: located_in
  review:
    summary: Redundant Reactome cytosol localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant cytosol annotation; genuine but non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871193
  qualifier: located_in
  review:
    summary: Redundant Reactome cytosol localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant cytosol annotation; genuine but non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871194
  qualifier: located_in
  review:
    summary: Redundant Reactome cytosol localization.
    action: KEEP_AS_NON_CORE
    reason: Redundant cytosol annotation; genuine but non-core.
    supported_by:
    - reference_id: file:human/DNAJC6/DNAJC6-goa.tsv
      supporting_text: cytosol
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:18489706
  title: Auxilin depletion causes self-assembly of clathrin into membraneless cages in vivo.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_18489706.md) PubMed title
      matches the YAML title exactly; abstract states auxilin is a cofactor for
      HSC70-mediated uncoating of clathrin-coated vesicles and that depletion blocks
      clathrin-mediated endocytosis, directly supporting DNAJC6's clathrin-uncoating
      co-chaperone core function."
  findings:
  - statement: Auxilin is a cofactor for HSC70-mediated uncoating of clathrin-coated vesicles; depletion of both auxilin isoforms inhibits clathrin-mediated endocytosis and causes formation of nonproductive membraneless clathrin cages.
    reference_section_type: ABSTRACT
- id: PMID:20160091
  title: Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publication (publications/PMID_20160091.md) PubMed title
      matches the YAML title exactly; abstract states auxilin acts as a co-chaperone
      supporting HSC70-dependent clathrin uncoating, and auxilin-knockout synapses
      accumulate clathrin-coated vesicles/empty cages with impaired endocytosis,
      directly supporting the clathrin-uncoating and synaptic-vesicle-recycling core
      functions (cited in core_functions)."
  findings:
  - statement: Auxilin and GAK act as co-chaperones supporting HSC70-dependent clathrin uncoating of clathrin-coated vesicles; auxilin-knockout synapses show increased clathrin-coated vesicles/empty cages and impaired synaptic vesicle endocytosis.
    reference_section_type: ABSTRACT
- id: PMID:29735704
  title: LRRK2 phosphorylation of auxilin mediates synaptic defects in dopaminergic neurons from patients with Parkinson's disease.
  findings:
  - statement: LRRK2 phosphorylates auxilin in its clathrin-binding domain, altering clathrin binding and disrupting synaptic vesicle endocytosis in PD dopaminergic neurons; auxilin interacts with the clathrin heavy chain CLTC.
    reference_section_type: RESULTS
- id: Reactome:R-HSA-421836
  title: Clathrin-mediated endocytosis (cytosol localization)
  findings: []
- id: Reactome:R-HSA-432688
  title: Vesicle biogenesis (cytosol localization)
  findings: []
- id: Reactome:R-HSA-8868658
  title: Clathrin-mediated endocytosis (cytosol localization)
  findings: []
- id: Reactome:R-HSA-8868659
  title: Clathrin-mediated endocytosis (cytosol localization)
  findings: []
- id: Reactome:R-HSA-8868660
  title: Clathrin-mediated endocytosis (cytosol localization)
  findings: []
- id: Reactome:R-HSA-8869438
  title: Clathrin-mediated endocytosis (cytosol localization)
  findings: []
- id: Reactome:R-HSA-8871193
  title: Clathrin-mediated endocytosis (cytosol localization)
  findings: []
- id: Reactome:R-HSA-8871194
  title: Clathrin-mediated endocytosis (cytosol localization)
  findings: []
- id: file:human/DNAJC6/DNAJC6-uniprot.txt
  title: UniProt entry O75061 (AUXI_HUMAN), auxilin
  findings:
  - statement: Auxilin recruits HSPA8/HSC70 to clathrin-coated vesicles and promotes the ATP-dependent dissociation of clathrin from CCVs; binds clathrin cages stoichiometrically; the J domain mediates HSPA8 interaction and is required for basket dissociation; mutations cause PARK19A/PARK19B Parkinson disease.
    reference_section_type: OTHER
core_functions:
- description: Clathrin-uncoating co-chaperone that binds the clathrin heavy chain and clathrin cages and, via its J domain, recruits HSPA8/HSC70 and stimulates its ATPase activity to drive ATP-dependent disassembly of the clathrin coat.
  molecular_function:
    id: GO:0032050
    label: clathrin heavy chain binding
  locations:
  - id: GO:0030136
    label: clathrin-coated vesicle
  supported_by:
  - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
    supporting_text: Interacts with CLTC; this interaction produces a local change in heavy-chain contacts
  - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
    supporting_text: binds tightly to the clathrin cages, at a
- description: HSP70/HSC70 co-chaperone activity, recruiting and stimulating the ATPase of HSPA8/HSC70 through its J domain to power clathrin coat disassembly.
  molecular_function:
    id: GO:0031072
    label: heat shock protein binding
  locations:
  - id: GO:0030136
    label: clathrin-coated vesicle
  supported_by:
  - reference_id: file:human/DNAJC6/DNAJC6-uniprot.txt
    supporting_text: Interacts with HSPA8/HSC70 in an ATP-dependent manner; this interaction stimulates the HSPA8's ATPase activity
- description: Drives clathrin coat disassembly / synaptic vesicle uncoating during clathrin-mediated endocytosis, supporting synaptic vesicle recycling at nerve terminals.
  molecular_function:
    id: GO:0031072
    label: heat shock protein binding
  locations:
  - id: GO:0098894
    label: extrinsic component of presynaptic endocytic zone membrane
  supported_by:
  - reference_id: PMID:20160091
    supporting_text: act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles
  directly_involved_in:
  - id: GO:0072318
    label: clathrin coat disassembly
proposed_new_terms: []
suggested_questions:
- question: Is the PTEN-like phosphatase domain of auxilin catalytically active, or does it function purely as a phosphoinositide-binding membrane-targeting module that times auxilin recruitment to coated vesicles?
- question: How does LRRK2-mediated phosphorylation of auxilin's clathrin-binding domain mechanistically convert into the synaptic vesicle endocytosis defects seen in Parkinson disease dopaminergic neurons?
- question: To what extent can the ubiquitous homolog GAK compensate for neuronal auxilin loss, and does incomplete compensation explain the dopaminergic-neuron vulnerability in PARK19?
suggested_experiments:
- description: Reconstituted clathrin-cage disassembly assays with purified auxilin (wild-type, J-domain HPD mutant, and PARK19 disease variants) plus HSPA8 and ATP to quantify uncoating activity and HSPA8 ATPase stimulation.
- description: Phosphatase activity assays on the auxilin PTEN-like domain against phosphoprotein and phosphoinositide substrates, with active-site (Cys164) mutants, to resolve whether it is a bona fide phosphatase or a degenerate lipid-binding domain.
- description: Live-cell imaging of clathrin and HSC70 dynamics in DNAJC6-knockout versus rescued neurons (wild-type vs PARK19 variants) to map the uncoating defect and test GAK compensation.