Affinage

YKT6

Synaptobrevin homolog YKT6 · UniProt O15498

Length
198 aa
Mass
22.4 kDa
Annotated
2026-04-28
57 papers in source corpus 30 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

YKT6 is a lipid-anchored R-SNARE that participates in multiple membrane fusion events across the secretory, endosomal, and autophagic pathways by cycling between an autoinhibited closed cytosolic form and an active open membrane-bound form. The longin domain folds back onto the SNARE motif to maintain the closed conformation, which is stabilized by farnesylation; phosphorylation by Atg1/ULK1 or Ca²⁺-dependent kinases triggers conformational opening, enabling sequential palmitoylation and double prenylation (farnesyl plus geranylgeranyl via GGTase-III) that anchor YKT6 to target membranes (PMID:15044687, PMID:33723042, PMID:33025734, PMID:40049413). In its membrane-bound form, YKT6 assembles into distinct quaternary SNARE complexes—with syntaxin 5/GS28/Bet1 for ER-to-Golgi transport, syntaxin 5/GS28/GS15 for intra-Golgi and endosome-to-TGN trafficking, and SNAP29/STX7 or a priming complex with STX17/SNAP29 (subsequently displaced by VAMP8) for autophagosome–lysosome fusion—and additionally mediates constitutive secretory vesicle fusion at the plasma membrane and Wnt recycling through endosomes (PMID:11323436, PMID:12388752, PMID:29789439, PMID:38340317, PMID:28403141, PMID:32611603). The longin domain also possesses an intrinsic palmitoyl-CoA binding activity that mediates self-palmitoylation and non-enzymatic palmitoyl transfer to substrates such as Vac8, linking YKT6 to protein lipidation during vacuole fusion (PMID:14685280, PMID:15479160). Homozygous loss-of-function variants in YKT6 cause a Mendelian disorder with neuronal and hepatic dysfunction, consistent with its essential role in autophagic flux (PMID:38522068).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 High

    Identifying YKT6 as a participant in ER-to-Golgi and vacuolar SNARE complexes established it as a versatile R-SNARE functioning at multiple trafficking steps rather than a single compartment.

    Evidence Co-IP of mammalian YKT6 with syntaxin 5/GS28/Bet1 plus antibody-mediated inhibition of ER-Golgi transport; yeast genetic suppressor screens linking Ykt6 to Vti1p-containing complexes at prevacuolar and vacuolar compartments

    PMID:11323436 PMID:11445562

    Open questions at the time
    • No structural information on how YKT6 discriminates among different SNARE partners
    • Mechanism of YKT6 membrane recruitment unknown at this stage
  2. 2002 High

    Discovery of a distinct syntaxin 5/GS28/Ykt6/GS15 complex at the medial Golgi and in endosome-to-TGN transport demonstrated that YKT6 participates in at least two non-overlapping quaternary SNARE complexes with shared Q-SNARE partners.

    Evidence Reciprocal Co-IP from Golgi extracts identifying GS15 as alternative to Bet1 in a YKT6-containing complex; in vitro transport assay with Shiga toxin B confirming each SNARE is required for EE/RE-to-TGN transport

    PMID:12388752 PMID:15215310

    Open questions at the time
    • Whether SNARE complex selectivity is achieved through spatial segregation or regulatory mechanisms was unresolved
  3. 2003 High

    Demonstrating that the longin domain controls subcellular targeting and that cytosolic YKT6 is conformationally inactive for SNARE assembly revealed the autoregulatory principle governing this SNARE, while the longin domain's ability to present palmitoyl-CoA to Vac8 uncovered an unexpected non-SNARE catalytic function.

    Evidence Neuronal localization, density gradient fractionation, and SNARE assembly assays showing longin-directed targeting; in vitro vacuole fusion assay demonstrating longin-dependent palmitoyl transfer to Vac8

    PMID:12589064 PMID:14685280

    Open questions at the time
    • Whether palmitoyl transfer activity extends to substrates beyond Vac8 was untested
    • Structural basis of palmitoyl-CoA binding not yet resolved
  4. 2004 High

    Systematic dissection of C-terminal lipid modifications established that farnesylation precedes palmitoylation, that double lipid modification is essential for membrane association and intra-Golgi transport, and that the longin domain possesses intrinsic self-palmitoylation activity—revealing the full lipid-modification cascade controlling YKT6 activation.

    Evidence Metabolic labeling, mutagenesis of lipidation sites, in vitro transport assays, and in vitro palmitoylation assays with recombinant protein

    PMID:15044687 PMID:15331663 PMID:15479160

    Open questions at the time
    • Identity of enzymes mediating palmitoylation/depalmitoylation cycles in vivo was unclear
    • Structural basis of closed conformation at atomic resolution was incomplete
  5. 2008 High

    The crystal structure of the yeast longin domain and biophysical characterization of farnesylated YKT6 provided the first atomic-level view of how the farnesyl group docks into a hydrophobic pocket to stabilize the closed conformation, while DHHC acyltransferase studies established that depalmitoylation-driven recycling prevents inappropriate membrane trapping.

    Evidence X-ray crystallography at 2.5 Å, CD spectroscopy, SEC, limited proteolysis, SPR for lipid binding; yeast DHHC overexpression showing missorting of longin-domain mutants into MVB pathway

    PMID:18329045 PMID:18541004

    Open questions at the time
    • Full-length structure of the closed state with both longin and SNARE domains was lacking
    • Kinetics and regulation of the palmitoylation/depalmitoylation cycle in vivo were unresolved
  6. 2016 Medium

    Single-molecule FRET demonstrated that YKT6 undergoes rapid (~200 μs) intramolecular conformational dynamics that are locked into a closed state by lipid (DPC), providing direct biophysical evidence for a lipid-regulated conformational switch.

    Evidence Single-molecule FRET and fluorescence cross-correlation spectroscopy on rat Ykt6 with DPC

    PMID:27493064

    Open questions at the time
    • DPC is a detergent surrogate; behavior on physiological lipid bilayers was not tested
    • Phosphorylation-mediated opening was not yet linked to this dynamic
  7. 2017 High

    Demonstrating that YKT6 serves as a v-SNARE for constitutive secretory vesicle fusion at the plasma membrane in both Drosophila and mammalian cells expanded its functional repertoire beyond Golgi and endosomal trafficking to the terminal secretory pathway.

    Evidence Combinatorial RNAi depletion with quantitative secretion assays in Drosophila S2 cells and mammalian cells

    PMID:28403141

    Open questions at the time
    • The cognate Q-SNARE partners for PM fusion were not defined
    • Whether YKT6 and VAMP3 act in parallel or sequential pathways at the PM was unclear
  8. 2018 High

    Multiple groups converged on YKT6 as an autophagosomal SNARE mediating autophagosome–lysosome/vacuole fusion, forming complexes with SNAP29/STX7 (mammals) and Syx17/Snap29 (Drosophila), with the finding that VAMP7/VAMP8 can outcompete YKT6 suggesting a priming or regulatory role; in vitro reconstitution with intact yeast autophagosomes confirmed Ykt6 as the R-SNARE requiring HOPS and Ypt7.

    Evidence STX17-KO plus YKT6 siRNA in HeLa; Drosophila loss-of-function genetics with rescue; novel in vitro autophagosome-vacuole fusion assay with purified organelles

    PMID:29694367 PMID:29789439 PMID:30097515

    Open questions at the time
    • Whether YKT6 is the primary fusogenic SNARE or a regulatory/priming SNARE was debated
    • Mechanism of YKT6 recruitment to autophagosomes was not fully defined
  9. 2019 High

    Linking α-synuclein pathology to aberrant inactivation of YKT6—and showing that farnesyltransferase inhibitors restore its membrane-bound active form and lysosomal function—established YKT6 as a convergent target in Parkinson's disease and revealed that lysosomal stress normally triggers YKT6 activation for hydrolase trafficking.

    Evidence Patient iPSC-derived neurons, co-immunoprecipitation of α-synuclein with YKT6, membrane fractionation, FTI treatment in cells and mice

    PMID:31648898

    Open questions at the time
    • Whether FTI-mediated activation of YKT6 is therapeutically viable long-term was untested
    • Direct phosphorylation events during lysosomal stress signaling were not mapped
  10. 2020 High

    Identification of Atg1/ULK1 phosphorylation as the switch that keeps autophagosomal YKT6 inactive until fusion is appropriate, and phosphorylation-dependent opening regulating Wnt recycling through endosomes, established phosphorylation as the master regulatory mechanism for YKT6's closed-to-open transition across pathways.

    Evidence In vitro kinase assays, phospho-site mutagenesis, genetic epistasis with Dsl1 complex for autophagosomal recruitment, Drosophila wing genetics for Wnt trafficking, proximity proteomics (BioID)

    PMID:32611603 PMID:33025734 PMID:33207719

    Open questions at the time
    • Identity of the phosphatase(s) that dephosphorylate YKT6 to permit fusion was unknown
    • Whether phosphorylation regulates the same residue across all trafficking pathways was unclear
  11. 2021 High

    NMR-resolved structural characterization confirmed a Ca²⁺-responsive phosphorylation-driven conformational switch, while identification of GGTase-III (PTAR1-dependent) as the enzyme mediating geranylgeranylation of the second cysteine established the full prenylation cascade required for lysosomal hydrolase sorting.

    Evidence NMR structural analysis with phospho-mimetic mutants; PTAR1-KO cells with cathepsin D/β-hexosaminidase secretion assays, LC3B accumulation, Golgi morphology

    PMID:33035318 PMID:33723042

    Open questions at the time
    • How GGTase-III accesses the farnesylated substrate in the context of the closed conformation was not structurally resolved
    • Whether double prenylation and palmitoylation are coordinated or independent was unclear
  12. 2023 High

    Reconstitution of the YKT6–STX17–SNAP29 priming complex and demonstration that VAMP8 displaces YKT6 to form the fusogenic complex resolved the longstanding question of whether YKT6 is a direct fusogenic SNARE or a priming factor in autophagosome–lysosome fusion, while human disease-causing YKT6 variants failed rescue in Drosophila, confirming its essential in vivo role.

    Evidence In vitro lipid and content mixing assays with reconstituted SNARE complexes; Drosophila genetic rescue with human variant constructs; single-molecule FRET with phospho-mimetic and species-specific mutants

    PMID:37380075 PMID:38340317 PMID:38522068

    Open questions at the time
    • Whether the priming mechanism applies at non-autophagosomal fusion steps is unknown
    • Full clinical spectrum of human YKT6 loss-of-function disease is not yet delineated
  13. 2025 Medium

    Localization of YKT6 to hippocampal synaptic spines and its requirement for LTP-dependent AMPA receptor insertion identified a neuronal trafficking function linking its SNARE activity to synaptic plasticity, and confirmed that α-synuclein pathology disrupts this process.

    Evidence Immunofluorescence, electrophysiology (mEPSC recording), LTP induction, surface receptor assays in hippocampal neurons; GGTase-III (Ecm9) knockout in yeast confirming conserved double prenylation requirement for autophagy

    PMID:40049413 PMID:40840626

    Open questions at the time
    • The specific SNARE complex mediating AMPA receptor exocytosis at synapses has not been identified
    • Whether YKT6 synaptic function depends on the same phospho-regulatory switch is untested
    • Single study for the synaptic plasticity phenotype

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the phosphatase(s) that dephosphorylate YKT6 to permit fusion, whether the priming mechanism (displacement by VAMP8) operates at non-autophagosomal fusion steps, the full-length atomic structure of YKT6 in both closed and open states on a membrane, and the complete clinical spectrum and pathomechanism of human YKT6 deficiency.
  • No phosphatase identified
  • No full-length membrane-bound structure
  • Human disease spectrum incompletely characterized
  • Priming-to-fusion handoff mechanism not tested outside autophagy

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 6 GO:0008289 lipid binding 3 GO:0016740 transferase activity 2
Localization
GO:0005794 Golgi apparatus 4 GO:0005829 cytosol 4 GO:0005773 vacuole 3 GO:0031410 cytoplasmic vesicle 3 GO:0005764 lysosome 2 GO:0005768 endosome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-9612973 Autophagy 7 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-162582 Signal Transduction 2 R-HSA-9609507 Protein localization 2 R-HSA-112316 Neuronal System 1
Partners
BET1BET1LGOSR1SNAP29SNCASTX17STX5STX7
Complex memberships
SNAP29-STX7-YKT6 SNARE complexSTX17-SNAP29-YKT6 priming complexSyntaxin5-GS28-Bet1-YKT6 SNARE complexSyntaxin5-GS28-GS15-YKT6 SNARE complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Mammalian YKT6 forms a SNARE complex with syntaxin 5, GS28, and Bet1, and functions at a late stage in ER-to-Golgi transport; antibodies against YKT6 inhibit in vitro ER-Golgi transport of VSVG before the EGTA-sensitive stage, and recombinant YKT6 blocks transport; YKT6 localizes primarily to Golgi membranes. Co-immunoprecipitation, in vitro transport assay with antibody inhibition, double-label immunofluorescence, microinjection The Journal of biological chemistry High 11323436
2001 Yeast YKT6 (R-SNARE) genetically interacts with the Q-SNARE VTI1 and functions in transport to the prevacuole/late endosome and vacuole in addition to retrograde traffic to the cis-Golgi; YKT6 participates in SNARE complexes containing Vti1p+Pep12p and Vti1p+Vam3p+Vam7p. Mutation of the 0-layer arginine in Ykt6 (R165Q) in complexes where it contributes a fourth glutamine renders the complex nonfunctional. Genetic suppressor screen (multicopy and low-copy), vacuolar transport assays, site-directed mutagenesis of 0-layer residues The Journal of biological chemistry High 11445562
2002 GS15 forms a distinct SNARE complex with syntaxin 5, GS28, and Ykt6 in the medial Golgi, implicating this quaternary complex in early cisternae trafficking; components of COPI coat co-immunoprecipitate selectively with GS15 from Golgi extracts. Co-immunoprecipitation, immuno-EM, siRNA knockdown, overexpression of dominant-negative mutants Molecular biology of the cell High 12388752
2003 Rat Ykt6 is a neuronal SNARE that localizes to a specialized punctate compartment distinct from known endomembrane organelles; its profilin-like longin domain directs this unique targeting even in the absence of prenylation; cytosolic Ykt6 is conformationally inactive for SNARE complex assembly. Immunofluorescence microscopy, density gradient fractionation, mutagenesis of longin domain and prenylation sites, SNARE complex assembly assays Molecular biology of the cell High 12589064
2003 Yeast Ykt6 mediates palmitoylation of the fusion factor Vac8 during homotypic vacuole fusion through a novel subreaction controlled by a Sec17-independent function of Sec18; the N-terminal longin domain of Ykt6 presents palmitoyl-CoA to Vac8, and transfer to Vac8's SH4 domain occurs spontaneously (non-enzymatically). In vitro vacuole fusion assay, biochemical fractionation, mutagenesis The EMBO journal High 14685280
2004 YKT6 exists as both cytosolic (inactive) and membrane-bound (active) forms; both are farnesylated at the C-terminal cysteine of CCAIM, and farnesylation is a prerequisite for subsequent palmitoylation of the upstream cysteine. Double lipid modification is required for intra-Golgi transport in vitro and cell viability. The N-terminal longin domain interacts with the SNARE motif to maintain YKT6 in a closed, inactive conformation, and conformational changes control lipid modification and membrane recruitment. In vitro transport assay, metabolic labeling, mutagenesis of lipidation sites, cell viability assay Proceedings of the National Academy of Sciences of the United States of America High 15044687
2004 The syntaxin 5/Ykt6/GS28/GS15 SNARE complex mediates transport from the early/recycling endosome to the trans-Golgi network (EE/RE-TGN); antibodies to each of these four SNAREs specifically inhibited this transport step in vitro; GS15 and Ykt6 redistribute from Golgi to endosomes when the recycling endosome is perturbed, suggesting cycling between these compartments. In vitro transport assay with Shiga toxin B subunit marker, antibody inhibition, siRNA knockdown of GS15, SNX3 overexpression morphological analysis Molecular biology of the cell High 15215310
2004 The longin domain of mammalian Ykt6 controls subcellular targeting through intramolecular protein-protein interactions with the SNARE motif and protein-lipid interactions with lipid groups at the C-terminus; two hydrophobic pockets on each face of the longin domain suppress mislocalization, and one suppresses palmitoylation-dependent mislocalization to the plasma membrane; both interactions maintain a compact closed conformation preventing premature membrane insertion. Mutagenesis of longin domain surface residues, immunofluorescence localization, co-immunoprecipitation of intramolecular interactions Journal of cell science High 15331663
2004 Human Ykt6 has intrinsic self-palmitoylating activity: the N-terminal longin domain contains a palmitoyl-CoA binding site required for covalent palmitoylation of its own C-terminal cysteine residues. In vitro palmitoylation assay with [3H]palmitoyl-CoA, recombinant protein mutagenesis The Biochemical journal High 15479160
2005 Yeast Ykt6 is released from vacuolar membranes during an early stage of vacuole fusion in a priming-dependent (SNARE disassembly-dependent) manner; yeast Ykt6 becomes palmitoylated in vitro at its C-terminal CAAX motif, and mutation of the palmitoylation site prevents stable membrane association and is lethal, suggesting depalmitoylation-driven recycling of this SNARE. In vitro vacuole fusion assay, palmitoylation assay, site-directed mutagenesis, cell viability EMBO reports High 15723044
2008 Farnesylation of Ykt6 (at the CAAX box) increases protein stability, helical content, and compactness as shown by CD spectroscopy, size exclusion chromatography, and limited proteolysis; farnesylated Ykt6 binds lipid membranes independently of membrane charge. The crystal structure of the yeast Ykt6 longin domain (residues 1–140) at 2.5 Å reveals a hydrophobic surface patch that accommodates the lipid moiety in the closed conformation. In vitro farnesylation, size exclusion chromatography, limited proteolysis, circular dichroism, surface plasmon resonance, X-ray crystallography at 2.5 Å Journal of molecular biology High 18329045
2008 Ykt6 cycles between cytosol and membranes through intramolecular interaction between its N-terminal longin domain and C-terminal SNARE domain; a mutant deficient in this intramolecular interaction accumulates stably on membranes and is not released from vacuoles. Ykt6 is a substrate of DHHC acyltransferases; overexpression of vacuolar acyltransferase Pfa3 drives a longin-domain mutant (F42S) into the vacuolar lumen, indicating that depalmitoylation is required to prevent Ykt6 entry into the MVB pathway. Mutagenesis, in vivo localization, vacuole fusion assay, DHHC acyltransferase overexpression Traffic (Copenhagen, Denmark) High 18541004
2016 Single-molecule FRET and FCCS demonstrate that rat Ykt6 undergoes intramolecular conformational dynamics between its longin domain and SNARE core at a timescale of ~200 μs; the presence of the lipid DPC eliminates this dynamics and locks Ykt6 in a closed conformation, supporting lipid-regulated conformational switching. Single-molecule FRET, Fluorescence Cross-Correlation Spectroscopy, molecular dynamics simulation Scientific reports Medium 27493064
2017 YKT6 and VAMP3/Synaptobrevin function as v-SNAREs in constitutive secretory vesicle fusion with the plasma membrane in both Drosophila and mammalian cells; RNAi depletion of YKT6 blocks constitutive secretion, identifying an evolutionarily conserved role of YKT6 in Golgi-to-PM transport. RNAi combinatorial depletion in Drosophila cells, quantitative secretion assay, RNAi in mammalian cells PLoS genetics High 28403141
2018 YKT6 is an autophagosomal SNARE protein that mediates autophagosome-lysosome fusion independently of STX17: YKT6 depletion partially blocks fusion in wild-type and completely blocks it in STX17-KO HeLa cells. YKT6 forms a SNARE complex with SNAP29 and lysosomal STX7 on autophagosomes. Recruitment to autophagosomes requires the N-terminal longin domain but not C-terminal palmitoylation/farnesylation. STX17 KO and YKT6 siRNA depletion in HeLa cells, autophagosome-lysosome fusion assay, Co-immunoprecipitation, domain mutagenesis The Journal of cell biology High 29789439
2018 In Drosophila, Ykt6 is required for autophagosome-lysosome fusion and localizes to lysosomes/autolysosomes; it forms a SNARE complex with Syx17 and Snap29. Vamp7 can outcompete Ykt6 from this complex, and Vamp7 overexpression rescues fusion defects in ykt6 mutants. An RQ mutation in the 0-layer of Ykt6 retains normal autophagic activity, suggesting Ykt6 acts as a non-canonical regulatory SNARE in this process; palmitoylation and farnesylation site mutants do not rescue. Drosophila genetics (loss-of-function mutants, rescue constructs), Co-immunoprecipitation, autophagic flux assays, site-directed mutagenesis PLoS genetics High 29694367
2018 A novel in vitro assay with intact yeast autophagosomes and vacuoles identifies Ykt6 as the autophagosomal R-SNARE; fusion requires ATP, physiological temperature, the HOPS tethering complex, Ypt7 GTPase, Mon1-Ccz1 GEF, and the entire fusion machinery. Novel in vitro autophagosome-vacuole fusion assay with purified organelles, genetic depletion of individual components The Journal of cell biology High 30097515
2019 Cytosolic ykt6 is normally autoinhibited by a farnesyl-mediated regulatory mechanism; during lysosomal stress, ykt6 activates and redistributes to membranes to promote lysosomal hydrolase trafficking and enhance cellular clearance. α-Synuclein aberrantly binds and deactivates ykt6 in patient-derived neurons, disabling the lysosomal stress response. Farnesyltransferase inhibitors activate ykt6 by promoting its membrane-bound open form, restoring lysosomal activity. Live-cell imaging, membrane fractionation, co-immunoprecipitation (α-syn binding to ykt6), patient iPSC-derived neurons, farnesyltransferase inhibitor treatment in cells and mice Neuron High 31648898
2020 Ykt6 function on autophagosomes is regulated by the Atg1 kinase complex through direct phosphorylation, keeping the Ykt6 pool on autophagosomal membranes inactive; dephosphorylation of Ykt6 is required for its engagement in autophagosome-vacuole fusion. Ykt6 is recruited to early autophagosome precursors through a mechanism requiring the ER-resident Dsl1 complex and COPII-coated vesicles. In vitro kinase assay (Atg1 phosphorylation of Ykt6), genetic epistasis (Dsl1 complex mutants), autophagy flux assays, Co-immunoprecipitation EMBO reports High 33025734
2020 Phosphorylation of Ykt6 in its SNARE domain mediates its conversion from a closed cytosolic to an open membrane-bound conformation, regulating membrane recruitment to multiple organelles; phosphorylated Ykt6 functionally regulates Wnt protein trafficking and extracellular vesicle secretion in Drosophila wing epithelium. Most Ykt6 is cytosolic but is recruited to de-acidified compartments to recycle Wnts via Rab4-positive recycling endosomes. Proximity-dependent proteomics (BioID), membrane fractionation, in vivo Drosophila genetics, in vitro biochemical analyses, phospho-site mutagenesis Biomolecules / Development High 32611603 33207719
2021 A conformational switch driven by phosphorylation at an evolutionarily conserved site (regulated by Ca2+ signaling) allows Ykt6 to transition from a closed cytosolic form to an open membrane-bound form; phosphorylated Ykt6 has an altered spectrum of protein interactions, causing defects in both secretory and autophagy pathways in Parkinson's disease models. NMR, biochemical assays, mutagenesis, Parkinson's disease cell models, Ca2+ signaling manipulation Proceedings of the National Academy of Sciences of the United States of America High 33723042
2021 Double prenylation of Ykt6 (farnesylation by FTase followed by geranylgeranylation by a novel GGTase-III containing PTAR1 subunit) at two C-terminal cysteines is required for proper lysosomal hydrolase trafficking; in PTAR1-KO cells (singly farnesylated Ykt6), cathepsin D and β-hexosaminidase are missorted and secreted extracellularly, Golgi structure is disrupted, and LC3B accumulates. PTAR1 gene knockout, lysosomal hydrolase secretion assay, autophagy flux assay (LC3B), Golgi morphology analysis Journal of biochemistry High 33035318
2023 Mammalian autophagosomal YKT6 is phosphorylated by ULK1 kinase, which prevents premature bundling with lysosomal SNARE proteins and inhibits autophagosome-lysosome fusion; alterations in YKT6 function produce both early and late autophagy defects in mammalian cells and C. elegans, reducing survival. In vitro ULK1 kinase assay, phospho-site mutagenesis, autophagy flux assays in mammalian cells and C. elegans, co-immunoprecipitation of SNARE complexes Journal of cell science High 36644903
2023 YKT6 forms a priming complex with STX17 and SNAP29 on autophagosomes via its SNARE domain; VAMP8 displaces YKT6 from this complex to form the fusogenic STX17-SNAP29-VAMP8 complex. The YKT6-SNAP29-STX17 complex facilitates both lipid and content mixing driven by STX17-SNAP29-VAMP8, demonstrating a priming role for YKT6 in efficient membrane fusion. Co-immunoprecipitation, lipid mixing assay, content mixing assay, domain mutagenesis, autophagy flux assays Cell reports High 38340317
2023 Homozygous missense variants in YKT6 (Tyr185Cys, Tyr64Cys) cause partial loss of function in Drosophila, failing to rescue lethality and autophagic flux defects in dYkt6 mutant flies, establishing YKT6 as essential for autophagic flux and neuronal/hepatic function in vivo. Drosophila genetic rescue with human variant constructs, autophagic flux assays, expression pattern analysis Genetics in medicine High 38522068
2023 Ykt6 conformational dynamics differ between yeast and rat: yeast Ykt6 adopts more open conformations and cannot bind DPC (which locks rat Ykt6 in a closed state); a T46L/Q57A point mutation converts yeast Ykt6 to a more closed, DPC-bound state. Phospho-mimic S174D shifts rat Ykt6 toward a more open state, confirming phosphorylation as a regulator of the closed-to-open conformational switch. Single-molecule FRET, biochemical characterization, molecular dynamics simulation, site-directed mutagenesis The Journal of biological chemistry High 37380075
2025 Ykt6 localizes to synaptic spines in mammalian hippocampus and regulates GluA1 and GluA2 glutamate receptor surface expression in an LTP-dependent manner; Ykt6 also modulates spine morphology, synaptic vesicle pool dynamics, and miniature EPSC amplitude and frequency. α-Synuclein pathology disrupts Ykt6 function and LTP. Immunofluorescence/live imaging, electrophysiology (mEPSC recording), LTP induction, surface receptor assays, loss-of-function studies The Journal of biological chemistry Medium 40840626
2025 Double prenylation (farnesyl + geranylgeranyl) is an evolutionarily conserved modification of Ykt6 in yeast, mediated by the GGTase-III complex consisting of Ecm9 (α subunit) and Bet2 (β subunit); loss of Ecm9 prevents double prenylation, impairs Ykt6 localization to organelle membranes including autophagosomes, and reduces autophagic activity and cell wall integrity. Structural prediction, in vitro prenylation assay, MALDI-TOF/TOF mass spectrometry, genetic deletion (ecm9Δ), autophagy assays The Journal of biological chemistry High 40049413
2018 Ykt6 regulates epithelial cell migration as a negative regulator; it upregulates microRNA-145 expression, which selectively decreases Junctional Adhesion Molecule A (JAM-A) levels, thereby limiting Rap1 and Rac1 small GTPase activity and attenuating cell spreading and motility. siRNA knockdown, overexpression, miRNA reporter assay, small GTPase activity assays, migration/invasion assays Cell cycle (Georgetown, Tex.) Medium 30010460

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Autophagosomal YKT6 is required for fusion with lysosomes independently of syntaxin 17. The Journal of cell biology 189 29789439
2004 Participation of the syntaxin 5/Ykt6/GS28/GS15 SNARE complex in transport from the early/recycling endosome to the trans-Golgi network. Molecular biology of the cell 135 15215310
2004 Localization and activity of the SNARE Ykt6 determined by its regulatory domain and palmitoylation. Proceedings of the National Academy of Sciences of the United States of America 121 15044687
2001 Ykt6 forms a SNARE complex with syntaxin 5, GS28, and Bet1 and participates in a late stage in endoplasmic reticulum-Golgi transport. The Journal of biological chemistry 113 11323436
2016 YKT6 expression, exosome release, and survival in non-small cell lung cancer. Oncotarget 106 27285987
2002 GS15 forms a SNARE complex with syntaxin 5, GS28, and Ykt6 and is implicated in traffic in the early cisternae of the Golgi apparatus. Molecular biology of the cell 104 12388752
2018 Non-canonical role of the SNARE protein Ykt6 in autophagosome-lysosome fusion. PLoS genetics 81 29694367
2001 Genetic interactions with the yeast Q-SNARE VTI1 reveal novel functions for the R-SNARE YKT6. The Journal of biological chemistry 81 11445562
2018 A novel in vitro assay reveals SNARE topology and the role of Ykt6 in autophagosome fusion with vacuoles. The Journal of cell biology 80 30097515
2003 Mammalian ykt6 is a neuronal SNARE targeted to a specialized compartment by its profilin-like amino terminal domain. Molecular biology of the cell 71 12589064
2003 The SNARE Ykt6 mediates protein palmitoylation during an early stage of homotypic vacuole fusion. The EMBO journal 71 14685280
2006 Possible involvement of CCT5, RGS3, and YKT6 genes up-regulated in p53-mutated tumors in resistance to docetaxel in human breast cancers. Breast cancer research and treatment 68 16821082
2020 LncRNA PVT1 promotes exosome secretion through YKT6, RAB7, and VAMP3 in pancreatic cancer. Aging 67 32499447
2019 Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein. Neuron 60 31648898
2004 Intramolecular protein-protein and protein-lipid interactions control the conformation and subcellular targeting of neuronal Ykt6. Journal of cell science 48 15331663
2019 The multi-functional SNARE protein Ykt6 in autophagosomal fusion processes. Cell cycle (Georgetown, Tex.) 37 30836834
2008 Farnesylation of the SNARE protein Ykt6 increases its stability and helical folding. Journal of molecular biology 37 18329045
2017 VAMP3/Syb and YKT6 are required for the fusion of constitutive secretory carriers with the plasma membrane. PLoS genetics 34 28403141
2008 Depalmitoylation of Ykt6 prevents its entry into the multivesicular body pathway. Traffic (Copenhagen, Denmark) 34 18541004
2005 The SNARE Ykt6 is released from yeast vacuoles during an early stage of fusion. EMBO reports 34 15723044
2020 Function of the SNARE Ykt6 on autophagosomes requires the Dsl1 complex and the Atg1 kinase complex. EMBO reports 32 33025734
2021 Tumor Suppressor miR-584-5p Inhibits Migration and Invasion in Smoking Related Non-Small Cell Lung Cancer Cells by Targeting YKT6. Cancers 27 33800298
2024 Human YKT6 forms priming complex with STX17 and SNAP29 to facilitate autophagosome-lysosome fusion. Cell reports 24 38340317
2004 The human SNARE protein Ykt6 mediates its own palmitoylation at C-terminal cysteine residues. The Biochemical journal 23 15479160
2021 A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6. Proceedings of the National Academy of Sciences of the United States of America 22 33723042
2020 Ykt6-dependent endosomal recycling is required for Wnt secretion in the Drosophila wing epithelium. Development (Cambridge, England) 22 32611603
2023 Impaired Autophagic-Lysosomal Fusion in Parkinson's Patient Midbrain Neurons Occurs through Loss of ykt6 and Is Rescued by Farnesyltransferase Inhibition. The Journal of neuroscience : the official journal of the Society for Neuroscience 21 36788031
2018 YKT6 as a second SNARE protein of mammalian autophagosomes. Autophagy 19 30290708
2010 Evidence for prenylation-dependent targeting of a Ykt6 SNARE in Plasmodium falciparum. Molecular and biochemical parasitology 19 21075148
2023 ULK1-mediated phosphorylation regulates the conserved role of YKT6 in autophagy. Journal of cell science 18 36644903
2021 Double prenylation of SNARE protein Ykt6 is required for lysosomal hydrolase trafficking. Journal of biochemistry 17 33035318
2023 A pan-cancer analysis of the oncogenic role of YKT6 in human tumors. Medicine 16 37058019
2018 Another longin SNARE for autophagosome-lysosome fusion-how does Ykt6 work? Autophagy 16 30290706
2020 Phosphorylation of Ykt6 SNARE Domain Regulates Its Membrane Recruitment and Activity. Biomolecules 15 33207719
2016 Lipid Regulated Intramolecular Conformational Dynamics of SNARE-Protein Ykt6. Scientific reports 15 27493064
2022 Unbalanced Regulation of Sec22b and Ykt6 Blocks Autophagosome Axonal Retrograde Flux in Neuronal Ischemia-Reperfusion Injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 35654605
2018 A membrane fusion protein, Ykt6, regulates epithelial cell migration via microRNA-mediated suppression of Junctional Adhesion Molecule A. Cell cycle (Georgetown, Tex.) 11 30010460
2014 Lipid regulated conformational dynamics of the longin SNARE protein Ykt6 revealed by molecular dynamics simulations. The journal of physical chemistry. A 11 25268560
2012 R-SNARE ykt6 resides in membrane-associated protease-resistant protein particles and modulates cell cycle progression when over-expressed. Biology of the cell 11 22443861
2018 Ykt6 mediates autophagosome-vacuole fusion. Molecular & cellular oncology 9 30525099
2021 The R-SNARE Ykt6 is required for multiple events during oogenesis in Drosophila. Cells & development 8 34856414
2023 Different conformational dynamics of SNARE protein Ykt6 among yeast and mammals. The Journal of biological chemistry 7 37380075
2017 Involvement of SNARE protein Ykt6 in glycosome biogenesis in Trypanosoma brucei. Molecular and biochemical parasitology 6 29107734
2022 Regulation of the SNARE protein Ykt6 function by diprenylation and phosphorylation. Journal of biochemistry 5 36166826
1999 Characterization of the sequence and expression of a Ykt6 prenylated SNARE from rat. DNA and cell biology 5 10073573
2025 Alpha-Synuclein Inhibits the Secretion of Extracellular Vesicles through Disruptions in YKT6 Lipidation. The Journal of neuroscience : the official journal of the Society for Neuroscience 4 39794126
2024 Ykt6 functionally overlaps with vacuolar and exocytic R-SNAREs in the yeast Saccharomyces cerevisiae. The Journal of biological chemistry 4 38588809
2024 miR-584-5p / Ykt6 - mediated autophagy - lysosome - exosome pathway as a critical route affecting the toxic effects of lead on HK-2 cells. Ecotoxicology and environmental safety 4 38636258
2025 Double prenylation of budding yeast Ykt6 regulates cell wall integrity and autophagy. The Journal of biological chemistry 3 40049413
2024 Homozygous missense variants in YKT6 result in loss of function and are associated with developmental delay, with or without severe infantile liver disease and risk for hepatocellular carcinoma. Genetics in medicine : official journal of the American College of Medical Genetics 3 38522068
2025 Use of Biotin-Labeled Geranyl Pyrophosphate for Analysis of Ykt6 Geranylgeranylation. Methods in molecular biology (Clifton, N.J.) 2 39806148
2025 MACC1 drives metastasis in colorectal cancer by coordinating YKT6-dependent exosome biogenesis and c-Met cargo selection. Cellular signalling 1 40834974
2025 The SNARE protein Ykt6 drives insertion of the GluA1 and GluA2 glutamate receptors at synaptic spines during long-term potentiation. The Journal of biological chemistry 1 40840626
2025 YKT6 Promotes Bladder Cancer Progression by Stabilizing β-catenin Through USP7-Mediated Deubiquitination. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41298248
2025 Ykt6 SNARE protein drives GluA1 insertion at synaptic spines during LTP. bioRxiv : the preprint server for biology 0 40236018
2025 Expression of DKK1, HOXC6, and YKT6 Genes in Subjects With Oral Squamous Cell Carcinoma Residing in Central India: A Case-Control Study. Cureus 0 41477365
2023 Conserved regulation of autophagosome-lysosome fusion through YKT6 phosphorylation. Autophagy reports 0 40395297