Synaptotagmin-4 (Syt IV) is a single-pass membrane protein of the synaptotagmin family, with a short intravesicular N-terminus and two cytoplasmic C2 domains. It is an activity-induced immediate early gene in neurons and neuroendocrine cells. Unlike Ca2+-sensing synaptotagmins, rat Syt4 has lost Ca2+ binding: its C2A carries an Asp-to-Ser (Ser244) substitution of a Ca2+ ligand and its C2B cannot form full Ca2+ sites, so it shows no Ca2+-dependent phospholipid binding. Syt4 binds syntaxins and t-SNARE heterodimers Ca2+-independently, inhibits SNARE-catalysed membrane fusion and competes with Ca2+-sensing synaptotagmins such as Syt1, Syt7 and Syt9. In cells it acts as a negative regulator of Ca2+-triggered dense-core vesicle exocytosis, including catecholamine and BDNF release, and it shapes fusion pores. On immature secretory granules it binds syntaxin 6 and is needed for their homotypic fusion and maturation. On neuronal dense-core vesicles it binds the kinesin KIF1A. Phosphorylation of Ser135 by JNK weakens this interaction, so dense-core vesicles are released from microtubule transport and captured at synapses. Syt4 is also found at the Golgi, in dendrites, axons and astrocyte processes, where it supports Ca2+-dependent glutamate release.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000149 SNARE binding | IBA GO_REF:0000033 | ACCEPT | Summary: Syt4 binds t-SNAREs and syntaxins Ca2+-independently; inherited family-wide SNARE binding. Reason: SNARE binding is the best-supported molecular activity of rat Syt4: it binds syntaxin 1A/SNAP-25 t-SNARE heterodimers strongly and Ca2+-independently (PMID:20688915, PMID:18508778) and binds syntaxins 1A, 2, 3, 4 and 6 (PMID:10397765, PMID:16618809). The PAINT node for the synaptotagmin family places SNARE binding deep in the family, and Syt4 retains it although it has lost Ca2+ regulation. RGD:68397 (Syt4 itself) appears among the IBD sources, which marks the experimental grounding on the target. Supporting Evidence: PMID:20688915 Rat SYT4 strongly bound to t-SNARE heterodimers in the absence Ca2+; binding was not influenced by the addition of Ca2+. PMID:18508778 also bound t-SNAREs and PS, but these interactions were not enhanced by Ca2+ PMID:10397765 the C2A domain of Syt IV binds syntaxin isoforms in a calcium-independent manner |
| GO:0000149 SNARE binding | IDA PMID:18508778 Analysis of the synaptotagmin family during reconstituted me... | ACCEPT | Summary: Reconstituted co-flotation assays show Syt IV binding to membrane-embedded syntaxin 1A/SNAP-25B, unaffected by Ca2+. Reason: Full text read. Bhalla et al. show that all syt isoforms tested, including Syt IV, bind t-SNARE heterodimers in liposomes, and that Syt IV binding is not enhanced by Ca2+. Syt IV also lowers Ca2+-promoted binding of Syt I to t-SNAREs, a competition that underlies its inhibitory effect on fusion. This is a core activity. Supporting Evidence: PMID:18508778 also bound t-SNAREs and PS, but these interactions were not enhanced by Ca2+ PMID:18508778 Thus, it appears that inhibitory isoforms of syt can impact fusion in two ways: first, they directly inhibit SNARE-mediated fusion, and second, they displace syt I from the fusion complex. |
| GO:0000149 SNARE binding | IPI PMID:20688915 Rat and Drosophila synaptotagmin 4 have opposite effects dur... | ACCEPT | Summary: Rat SYT4 binds t-SNARE (syntaxin 1A/SNAP-25) heterodimers strongly in the absence of Ca2+. Reason: Full text read. Wang and Chapman show strong Ca2+-independent binding of rat SYT4 to t-SNARE heterodimers reconstituted in PS-free liposomes, with syntaxin 1A (P32851) and SNAP-25 (P60881) as the With/From partners. This is the core molecular activity behind its inhibition of fusion. Supporting Evidence: PMID:20688915 Rat SYT4 strongly bound to t-SNARE heterodimers in the absence Ca2+; binding was not influenced by the addition of Ca2+. PMID:20688915 We report that rat SYT4 inhibited SNARE-catalyzed membrane fusion in both the absence and presence of Ca(2+). |
| GO:0001786 phosphatidylserine binding | IDA PMID:18508778 Analysis of the synaptotagmin family during reconstituted me... | UNDECIDED | Summary: Co-flotation shows weak, Ca2+-independent binding of Syt IV to PS-containing liposomes; contradicted by later co-sedimentation data. Reason: Full text read. Bhalla et al. found that all isoforms tested, Syt IV included, show some PS and t-SNARE binding without Ca2+, and that Ca2+ does not enhance it for Syt IV. A later co-sedimentation study from the same lab found no PS binding by rat SYT4 with or without Ca2+ (PMID:20688915), and Dai et al. found no efficient phospholipid binding (PMID:15311271). The weak Ca2+-independent binding is an experimental observation the curator correctly captured. The two assays from the same laboratory disagree on whether rat Syt4 binds PS at all in the absence of Ca2+, and the evidence does not settle it, so this is left undecided. Both agree that Ca2+-dependent PS binding, the effector interaction behind synaptotagmin Ca2+-sensor function, is absent (accepted NOT rows). Supporting Evidence: PMID:18508778 also bound t-SNAREs and PS, but these interactions were not enhanced by Ca2+ PMID:20688915 Using this approach we found that rat SYT4 failed to bind to PS in either the absence or presence of Ca2+. |
| GO:0001786 phosphatidylserine binding | IDA NOT PMID:20688915 Rat and Drosophila synaptotagmin 4 have opposite effects dur... | ACCEPT | Summary: Rat SYT4 failed to bind PS liposomes in co-sedimentation, with or without Ca2+. Reason: Full text read. The negation captures the functionally important point that rat Syt4 lacks the Ca2+-triggered PS binding by which Ca2+-sensing synaptotagmins drive fusion. It agrees with PMID:15311271 and PMID:9162066. The Bhalla et al. co-flotation data (PMID:18508778) detected weak Ca2+-independent PS binding, so the two assays disagree on residual basal binding but agree on the absence of Ca2+-dependent binding. Supporting Evidence: PMID:20688915 Using this approach we found that rat SYT4 failed to bind to PS in either the absence or presence of Ca2+. PMID:15311271 neither C(2) domain of rat synaptotagmin 4 binds Ca(2+) or phospholipids efficiently |
| GO:0005509 calcium ion binding | IDA NOT PMID:15311271 Structural basis for the evolutionary inactivation of Ca2+ b... | ACCEPT | Summary: Crystallography and binding assays show that neither rat Syt4 C2 domain forms full Ca2+-binding sites. Reason: Abstract states the result directly: neither C2 domain of rat synaptotagmin 4 binds Ca2+ efficiently, and the C2B ligands are misoriented. This agrees with the C2A Asp-to-Ser (Ser244) substitution data (PMID:9162066, PMID:7993622) and the UniProt function statement. The NOT annotation is well supported. Supporting Evidence: PMID:15311271 neither C(2) domain of rat synaptotagmin 4 binds Ca(2+) or phospholipids efficiently PMID:15311271 render the rat synaptotagmin 4 C(2)B domain unable to form full Ca(2+)-binding sites PMID:9162066 wild type C2A-domains of synaptotagmins IV and XI exhibited no Ca2+-dependent phospholipid binding PMID:7993622 whereas that of synaptotagmin IV is unable to bind Ca2+ |
| GO:0005509 calcium ion binding | ISO GO_REF:0000121 | REMOVE | Summary: ISO from mouse Syt4 calcium ion binding (mouse IDA, PMID:15197251); contradicted by direct structural and biochemical evidence on rat Syt4. Reason: Mouse and rat Syt4 are nearly identical, so the question is whether Syt4 binds Ca2+ at all. Direct structural and biochemical work on rat Syt4 shows that neither C2 domain forms a full Ca2+-binding site (PMID:15311271), and C2A has the inactivating Asp-to-Ser substitution (PMID:9162066). The mouse donor is a cell-biology paper on glial glutamate release that treats C2B as only a putative Ca2+-binding domain. Older reports of Ca2+-promoted C2B oligomerisation (PMID:10397765, PMID:9830048) predate the crystal structure and did not measure Ca2+ binding directly. The ISO transfer contradicts the direct NOT evidence on the target (PMID:15311271, accepted), so it is removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK FUNCTIONAL DIVERGENCE Sources checked: MGI:MGI:101759 SOURCE WEAK OR INFERRED Mouse IDA on PMID:15197251, a glial-release study that calls C2B the only putative Ca2+-binding domain; it is contradicted by direct Ca2+-binding and structural work on the near-identical rat protein. Supporting Evidence: PMID:15311271 neither C(2) domain of rat synaptotagmin 4 binds Ca(2+) or phospholipids efficiently PMID:15311271 render the rat synaptotagmin 4 C(2)B domain unable to form full Ca(2+)-binding sites file:rat/Syt4/Syt4-uniprot.txt Synaptotagmin family member which does not bind Ca(2+) |
| GO:0005515 protein binding | IPI PMID:18046461 JNK phosphorylates synaptotagmin-4 and enhances Ca2+-evoked ... | REMOVE | Summary: IntAct IPI, Syt4 with Syt1 (P21707). Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is real and is captured by a more informative term elsewhere in this review. Syt4-Syt1 hetero-oligomerisation is covered by the protein heterodimerization activity row (PMID:10397765). Supporting Evidence: PMID:10397765 the C2B domain of Syt IV contains calcium binding properties, which permit homo-oligomerization as well as hetero-oligomerization with Syt I |
| GO:0005515 protein binding | IPI PMID:18046461 JNK phosphorylates synaptotagmin-4 and enhances Ca2+-evoked ... | REMOVE | Summary: IntAct IPI, Syt4 with JNK1/MAPK8 (P49185). Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is real and is captured by a more informative term elsewhere in this review. JNK binds and phosphorylates Syt4 at Ser135 (PMID:18046461, abstract). This is an enzyme-substrate interaction recorded in the core-function description, not a Syt4 activity. Supporting Evidence: PMID:18046461 JNK associated with phosphorylated synaptotagmin-4 (Syt 4) PMID:18046461 NGF treatment led to phosphorylation of endogenous Syt 4 at Ser135 |
| GO:0005515 protein binding | IPI PMID:18046461 JNK phosphorylates synaptotagmin-4 and enhances Ca2+-evoked ... | REMOVE | Summary: IntAct IPI, Syt4 with JNK3/MAPK10 (P49187). Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is real and is captured by a more informative term elsewhere in this review. As for JNK1, this is a kinase-substrate interaction (PMID:18046461). Supporting Evidence: PMID:18046461 JNK associated with phosphorylated synaptotagmin-4 (Syt 4) |
| GO:0005515 protein binding | IPI PMID:29166604 Capture of Dense Core Vesicles at Synapses by JNK-Dependent ... | REMOVE | Summary: UniProt IPI, Syt4 with KIF1A (F1M4A4). Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is real and is captured by a more informative term elsewhere in this review. The Syt4-KIF1A interaction is proposed instead as a NEW kinesin binding (GO:0019894) row. Supporting Evidence: PMID:29166604 Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction PMID:29166604 indicating that Kif1A is the motor protein that transports Syt4-harboring DCVs |
| GO:0005515 protein binding | IPI PMID:30021165 Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca(... | REMOVE | Summary: UniProt IPI with With/From TANC2 (F1LTE0); the paper shows Syt4 co-purifying with KIF1A, not TANC2. Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is real and is captured by a more informative term elsewhere in this review. Stucchi et al. report Syt4 among Ca2+-dependent KIF1A interactors and pull down mCherry-Syt4 with a KIF1A tail fragment. TANC2 and liprin-alpha are KIF1A partners that the paper says are not part of the KIF1A-cargo complex, and no Syt4-TANC2 binding is shown. The With/From is therefore probably mis-keyed to TANC2 instead of KIF1A. Supporting Evidence: PMID:30021165 Only in the presence of calcium KIF1A(657-1698) associated with specific DCV-related proteins such as Syt4 and synaptotagmin 11 (Syt11) |
| GO:0005515 protein binding | IPI PMID:9830048 Delineation of the oligomerization, AP-2 binding, and synpri... | REMOVE | Summary: IPI, Syt4 with Syt1 (P21707): Ca2+-promoted hetero-oligomerisation. Reason: Bare protein binding is uninformative and is removed under the protein-binding policy. The interaction itself is real and is captured by a more informative term elsewhere in this review. Covered by protein heterodimerization activity (PMID:10397765). Supporting Evidence: PMID:9830048 Ca2+ promoted the hetero-oligomerization of synaptotagmin I with synaptotagmins III and IV |
| GO:0005543 phospholipid binding | IDA NOT PMID:9830048 Delineation of the oligomerization, AP-2 binding, and synpri... | ACCEPT | Summary: NOT phospholipid binding (Chapman 1998, abstract only). Reason: Abstract only; the abstract does not describe the lipid assay. The claim is independently supported for rat Syt4: neither C2 domain binds phospholipids efficiently (PMID:15311271), and rat SYT4 does not bind PS in co-sedimentation (PMID:20688915). The weak Ca2+-independent PS binding in co-flotation (PMID:18508778) is a caveat recorded on that row. Deferring to the curator. Supporting Evidence: PMID:15311271 neither C(2) domain of rat synaptotagmin 4 binds Ca(2+) or phospholipids efficiently PMID:20688915 Using this approach we found that rat SYT4 failed to bind to PS in either the absence or presence of Ca2+. |
| GO:0005544 calcium-dependent phospholipid binding | IDA NOT PMID:7791877 Ca(2+)-dependent and -independent activities of neural and n... | ACCEPT | Summary: NOT calcium-dependent phospholipid binding: Syt IV C2A does not bind phospholipids in a Ca2+-dependent manner. Reason: Abstract states that the first C2 domain of Syt IV, unlike those of Syt I, II, III, V and VII, does not bind phospholipids Ca2+-dependently. This agrees with PMID:9162066, PMID:15311271 and PMID:20688915. It is the defining biochemical feature of this inhibitory isoform. Supporting Evidence: PMID:7791877 The first C2 domains of Syt I, II, III, V and VII, but not of IV, VI or VIII, bind phospholipids with a similar Ca(2+)-concentration dependence PMID:9162066 wild type C2A-domains of synaptotagmins IV and XI exhibited no Ca2+-dependent phospholipid binding file:rat/Syt4/Syt4-uniprot.txt the first C2 domain/C2A does not bind Ca(2+) neither mediates Ca(2+)-dependent phospholipid binding |
| GO:0005544 calcium-dependent phospholipid binding | ISO GO_REF:0000121 | REMOVE | Summary: ISO from mouse calcium-dependent phospholipid binding; contradicted by direct rat Syt4 biochemistry. Reason: Five independent studies on rat Syt4 show no Ca2+-dependent phospholipid binding by C2A, by C2B or by the cytoplasmic domain (PMID:7791877, PMID:9162066, PMID:15311271, PMID:18508778, PMID:20688915). Only the S244D revertant gains it. Because the rat and mouse proteins are nearly identical, this ISO transfer contradicts direct evidence on the target and is removed. The contradicting NOT annotation (PMID:7791877) is accepted. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: FUNCTIONAL DIVERGENCE Sources checked: MGI:MGI:101759 SOURCE WEAK OR INFERRED Mouse IDA (PMID:8626542) not inspected; the near-identical rat protein lacks Ca2+-dependent phospholipid binding in multiple direct assays. Supporting Evidence: PMID:7791877 The first C2 domains of Syt I, II, III, V and VII, but not of IV, VI or VIII, bind phospholipids with a similar Ca(2+)-concentration dependence PMID:15311271 neither C(2) domain of rat synaptotagmin 4 binds Ca(2+) or phospholipids efficiently PMID:20688915 Using this approach we found that rat SYT4 failed to bind to PS in either the absence or presence of Ca2+. PMID:20688915 Rat SYT4 was able to stimulate fusion in response to Ca(2+) when the conserved Asp-to-Ser Ca(2+) ligand substitution in its C2A domain was reversed. |
| GO:0005794 Golgi apparatus | IDA PMID:10646502 Synaptotagmin IV is present at the Golgi and distal parts of... | KEEP AS NON CORE | Summary: Immunocytochemistry places SytIV at the Golgi and distal neurites in PC12 cells and hippocampal neurons. Reason: Abstract states Golgi localisation by isoform-specific immunostaining. Golgi is a root organelle term and is informative. Syt4 is synthesised and concentrated at the Golgi/TGN, where dense-core and immature secretory granules form, but its functions act on post-Golgi granules, so this location is non-core. Supporting Evidence: PMID:10646502 SytIV was localized at the Golgi and distal part of neurites in nerve growth factor-differentiated PC12 cells and cultured hippocampal neurons |
| GO:0005794 Golgi apparatus | IDA PMID:16618809 Synaptotagmin IV is necessary for the maturation of secretor... | KEEP AS NON CORE | Summary: Syt IV fractionates with ISGs and Golgi-containing fractions in PC12 cells. Reason: Full text: Syt IV is found mainly in ISG fractions and also in Golgi-containing fractions. Golgi is a root organelle term and is informative. Syt4 is synthesised and concentrated at the Golgi/TGN, where dense-core and immature secretory granules form, but its functions act on post-Golgi granules, so this location is non-core. Supporting Evidence: PMID:16618809 Syt IV was found mainly in the light ISG-containing fractions, as well as in Golgi-containing fractions |
| GO:0005794 Golgi apparatus | IDA PMID:26750488 Upregulation and axonal transport of synaptotagmin-IV in the... | KEEP AS NON CORE | Summary: IDA Golgi localisation in rat striatal neurons (abstract only). Reason: Abstract only; the abstract does not mention the Golgi, but the location is independently established (PMID:10646502, PMID:16618809). Deferring to the curator. Golgi is a root organelle term and is informative. Syt4 is synthesised and concentrated at the Golgi/TGN, where dense-core and immature secretory granules form, but its functions act on post-Golgi granules, so this location is non-core. Supporting Evidence: PMID:10646502 SytIV was localized at the Golgi and distal part of neurites in nerve growth factor-differentiated PC12 cells and cultured hippocampal neurons PMID:16618809 Syt IV was found mainly in the light ISG-containing fractions, as well as in Golgi-containing fractions |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of mouse Golgi localisation. Reason: The source is mouse Syt4 (P40749) with Golgi IDA (PMID:12135783, PMID:19448629); the rat protein is independently shown at the Golgi (PMID:10646502). The organelle claim holds. Golgi is a root organelle term and is informative. Syt4 is synthesised and concentrated at the Golgi/TGN, where dense-core and immature secretory granules form, but its functions act on post-Golgi granules, so this location is non-core. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. PMID:10646502 SytIV was localized at the Golgi and distal part of neurites in nerve growth factor-differentiated PC12 cells and cultured hippocampal neurons |
| GO:0005794 Golgi apparatus | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of mouse Golgi localisation. Reason: Mouse Syt4 is localised to the Golgi by EM (PMID:12135783), and rat Syt4 is independently localised there (PMID:10646502). The organelle claim holds. Golgi is a root organelle term and is informative. Syt4 is synthesised and concentrated at the Golgi/TGN, where dense-core and immature secretory granules form, but its functions act on post-Golgi granules, so this location is non-core. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. PMID:10646502 SytIV was localized at the Golgi and distal part of neurites in nerve growth factor-differentiated PC12 cells and cultured hippocampal neurons |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA plasma membrane (is_active_in) from the synaptotagmin family node. Reason: Syt4 is a vesicle membrane protein (DCV and ISG membranes; PMID:29166604, PMID:16618809, PMID:19448629). Plasma-membrane presence would only be transient after exocytosis, and no rat study reports it as a site of Syt4 function. The family-level plasma-membrane assertion reflects isoforms such as Syt7 that act on the plasma membrane. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000001283 SUPPORTS SOURCE BUT NOT TARGET Plasma-membrane activity is seeded by plasma-membrane synaptotagmins; Syt4 acts from DCV and ISG membranes. Supporting Evidence: file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane PMID:29166604 Syt4 was highly co-localized with CgA |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of mouse plasma-membrane localisation. Reason: Syt4 is a vesicle membrane protein (DCV and ISG membranes; PMID:29166604, PMID:16618809, PMID:19448629). Plasma-membrane presence would only be transient after exocytosis, and no rat study reports it as a site of Syt4 function. The family-level plasma-membrane assertion reflects isoforms such as Syt7 that act on the plasma membrane. Supporting Evidence: file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane PMID:19448629 We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: RGD ISO of mouse plasma-membrane localisation. Reason: Syt4 is a vesicle membrane protein (DCV and ISG membranes; PMID:29166604, PMID:16618809, PMID:19448629). Plasma-membrane presence would only be transient after exocytosis, and no rat study reports it as a site of Syt4 function. The family-level plasma-membrane assertion reflects isoforms such as Syt7 that act on the plasma membrane. The mouse donor (ARUK-UCL IDA, PMID:12135783) is an EM study whose abstract reports dendrites, axons, Golgi and vesicles, not the plasma membrane. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: MGI:MGI:101759 SOURCE WEAK OR INFERRED Mouse plasma-membrane IDA (PMID:12135783); the abstract places Syt4 on vesicles/organelles, dendrites, axons and Golgi. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane |
| GO:0006906 vesicle fusion | IBA GO_REF:0000033 | MODIFY | Summary: IBA vesicle fusion; Syt4 is needed for homotypic fusion of immature secretory granules. Reason: The family-level vesicle fusion term holds for Syt4 only in one context: siRNA depletion of Syt IV inhibits ISG homotypic fusion (PMID:16618809). In exocytic fusion Syt4 is inhibitory, which is captured by the negative-regulation terms. The supported specific descendant, which the gene already carries, is vesicle fusion with vesicle (GO:0061782). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH REGULATORY SIGN INVERSION Sources checked: PANTHER:PTN001597973 SUPPORTS TRANSFER Node includes RGD:68397 (Syt4) among its sources; for Syt4 the supported fusion role is ISG homotypic fusion, and exocytic fusion is inhibited. Proposed replacements: vesicle fusion with vesicle Supporting Evidence: PMID:16618809 ISG homotypic fusion was inhibited in vivo by small interfering RNA-mediated depletion of Syt IV. |
| GO:0007269 neurotransmitter secretion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: ISO of mouse acts_upstream_of_or_within neurotransmitter secretion (astrocyte glutamate release). Reason: Syt IV knockdown in astrocytes reduces Ca2+-dependent glutamate release (PMID:15197251), and Syt4 modulates catecholamine release in PC12 cells. This is a real but context-specific involvement. The core of Syt4 activity is negative regulation of DCV exocytosis. Supporting Evidence: PMID:15197251 Reduction of Syt IV in astrocytes by RNA interference decreases Ca(2+)-dependent glutamate release |
| GO:0007269 neurotransmitter secretion | NAS PMID:7892240 Synaptotagmin IV is an immediate early gene induced by depol... | KEEP AS NON CORE | Summary: NAS neurotransmitter secretion from the 1995 cloning paper. Reason: The cloning paper proposes a role in depolarization-induced, Ca2+-mediated exocytosis based on family membership. Later work shows Syt4 modulates (mostly inhibits) transmitter and peptide release (PMID:20735850, PMID:10397765), so involvement in secretion holds but is non-core and regulatory. Supporting Evidence: PMID:20735850 These data support an inhibitory effect of syt IV on release of vesicles and their transmitter content. PMID:10397765 Microinjection of the C2A domain reveals that calcium-independent interactions mediated through this domain of Syt IV inhibit calcium-mediated neurotransmitter release from PC12 cells. |
| GO:0007613 memory | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of mouse memory (knockout phenotype). Reason: Syt4 knockout mice have deficits in associative passive-avoidance memory (PMID:15390175). This is an organism-level phenotype downstream of altered BDNF release and plasticity, so it is kept as non-core. Supporting Evidence: PMID:15390175 we find that Syt IV (-/-) mice have deficits in the associative passive avoidance memory paradigm |
| GO:0007613 memory | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of mouse memory (knockout phenotype). Reason: Mouse knockout memory deficit (PMID:15390175); an organism-level phenotype, non-core. Supporting Evidence: PMID:15390175 we find that Syt IV (-/-) mice have deficits in the associative passive avoidance memory paradigm |
| GO:0008021 synaptic vesicle | IDA PMID:10217258 Synthesis degradation, and subcellular localization of synap... | MARK AS OVER ANNOTATED | Summary: Fractionation/immunoisolation places Syt IV in PC12 synaptic-like microvesicles and secretory granules (abstract only). Reason: Abstract only. The data support synaptic-like microvesicles of PC12 cells, which GO synaptic vesicle (part of a chemical synapse) does not strictly describe. In neurons, Syt4 is not a synaptic vesicle protein: EM and fractionation in mouse neocortex find no Syt4 on synaptic vesicles (PMID:12135783), it is absent from hippocampal presynaptic terminals (PMID:15197251), and it sits on BDNF-containing DCVs (PMID:19448629, PMID:29166604). The PC12 "synaptic-like microvesicles" in which Syt IV fractionates are a neuroendocrine vesicle class, not neuronal synaptic vesicles. The full text is not available, so the row is marked over-annotated rather than removed. Supporting Evidence: PMID:10217258 suggest that Syt IV protein is present in both synaptic-like microvesicles and secretory granules PMID:12135783 EM and cell fractionation studies showed no Syt IV signals at synaptic vesicles |
| GO:0008021 synaptic vesicle | ISO NOT GO_REF:0000121 | ACCEPT | Summary: NOT located in synaptic vesicle, transferred from mouse EM/fractionation (PMID:12135783). Reason: In neurons, Syt4 is not a synaptic vesicle protein: EM and fractionation in mouse neocortex find no Syt4 on synaptic vesicles (PMID:12135783), it is absent from hippocampal presynaptic terminals (PMID:15197251), and it sits on BDNF-containing DCVs (PMID:19448629, PMID:29166604). The PC12 "synaptic-like microvesicles" in which Syt IV fractionates are a neuroendocrine vesicle class, not neuronal synaptic vesicles. Supporting Evidence: PMID:12135783 EM and cell fractionation studies showed no Syt IV signals at synaptic vesicles PMID:15197251 Syt IV is expressed predominantly by astrocytes and is not in the presynaptic terminals of the hippocampus |
| GO:0008021 synaptic vesicle | NAS PMID:7892240 Synaptotagmin IV is an immediate early gene induced by depol... | MARK AS OVER ANNOTATED | Summary: NAS synaptic vesicle from the cloning paper (family-based statement). Reason: The 1995 paper describes synaptotagmins generically as synaptic vesicle proteins. In neurons, Syt4 is not a synaptic vesicle protein: EM and fractionation in mouse neocortex find no Syt4 on synaptic vesicles (PMID:12135783), it is absent from hippocampal presynaptic terminals (PMID:15197251), and it sits on BDNF-containing DCVs (PMID:19448629, PMID:29166604). The PC12 "synaptic-like microvesicles" in which Syt IV fractionates are a neuroendocrine vesicle class, not neuronal synaptic vesicles. Supporting Evidence: PMID:12135783 EM and cell fractionation studies showed no Syt IV signals at synaptic vesicles PMID:19448629 We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. |
| GO:0014049 positive regulation of glutamate secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of positive regulation of glutamate secretion (astrocytes). Reason: Knockdown of Syt IV in astrocytes reduces Ca2+-dependent glutamate release (PMID:15197251, rat astrocyte cultures). This is a real but cell-type-specific role. Supporting Evidence: PMID:15197251 Reduction of Syt IV in astrocytes by RNA interference decreases Ca(2+)-dependent glutamate release |
| GO:0014049 positive regulation of glutamate secretion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of positive regulation of glutamate secretion. Reason: As above: Syt IV supports Ca2+-dependent gliotransmitter glutamate release (PMID:15197251). Supporting Evidence: PMID:15197251 Reduction of Syt IV in astrocytes by RNA interference decreases Ca(2+)-dependent glutamate release |
| GO:0014059 regulation of dopamine secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of regulation of dopamine secretion (somatodendritic DA release). Reason: Down-regulating Syt4 and Syt7 reduced somatodendritic dopamine release in dopaminergic neurons (PMID:21576241, abstract). This is a context-specific secretory role, non-core. Supporting Evidence: PMID:21576241 Down-regulation of the dendritically expressed Syt4 and Syt7 severely reduced STD DA release |
| GO:0014059 regulation of dopamine secretion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of regulation of dopamine secretion. Reason: As above (PMID:21576241). Supporting Evidence: PMID:21576241 Down-regulation of the dendritically expressed Syt4 and Syt7 severely reduced STD DA release |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO membrane. Reason: Correct but uninformative: Syt4 is a single-pass membrane protein of dense-core vesicles and immature secretory granules. Replaced by the specific membranes it is shown on (neuronal DCV membrane, PMID:29166604; secretory granule membrane, PMID:16618809), both already on the gene. Proposed replacements: neuronal dense core vesicle membrane secretory granule membrane Supporting Evidence: file:rat/Syt4/Syt4-uniprot.txt Single-pass membrane protein file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane |
| GO:0016020 membrane | NAS PMID:7892240 Synaptotagmin IV is an immediate early gene induced by depol... | MODIFY | Summary: NAS membrane from the cloning paper. Reason: Correct but uninformative: Syt4 is a single-pass membrane protein of dense-core vesicles and immature secretory granules. Replaced by the specific membranes it is shown on (neuronal DCV membrane, PMID:29166604; secretory granule membrane, PMID:16618809), both already on the gene. Proposed replacements: neuronal dense core vesicle membrane secretory granule membrane Supporting Evidence: file:rat/Syt4/Syt4-uniprot.txt Single-pass membrane protein PMID:16618809 We present evidence that the ISG-localized synaptotagmin IV (Syt IV) is involved in ISG maturation. |
| GO:0016192 vesicle-mediated transport | IBA GO_REF:0000033 | MODIFY | Summary: IBA vesicle-mediated transport. Reason: True but very broad. The vesicle-trafficking step in which Syt4 is shown to take part as a positive participant is homotypic fusion of immature secretory granules (PMID:16618809), GO:0061782, an is_a descendant already on the gene. Its role in DCV transport is captured separately by dense core granule cytoskeletal transport. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000001283 SUPPORTS TRANSFER Family-level vesicle trafficking holds for Syt4, but more specific supported terms exist. Proposed replacements: vesicle fusion with vesicle Supporting Evidence: PMID:16618809 ISG homotypic fusion was inhibited in vivo by small interfering RNA-mediated depletion of Syt IV. |
| GO:0017075 syntaxin-1 binding | IPI PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | ACCEPT | Summary: Syt IV C2A binds syntaxin 1A Ca2+-independently. Reason: Full text read: GST-Syt IV C2A binds syntaxin 1A without Ca2+. This agrees with t-SNARE binding in reconstituted systems (PMID:20688915). Supporting Evidence: PMID:10397765 the C2A domain of Syt IV binds syntaxin isoforms in a calcium-independent manner |
| GO:0017156 calcium-ion regulated exocytosis | NAS PMID:7892240 Synaptotagmin IV is an immediate early gene induced by depol... | MODIFY | Summary: NAS calcium-ion regulated exocytosis from the cloning paper. Reason: Syt4 does not drive Ca2+-regulated exocytosis as a Ca2+ sensor. It is a negative regulator of Ca2+-triggered DCV exocytosis, inhibiting SNARE fusion and Syt I/VII/IX-driven fusion (PMID:18508778, PMID:21551071, PMID:20303854). The essence (Syt4 acts in regulated exocytosis) is right, so the row is refined to the regulatory term. Proposed replacements: negative regulation of calcium ion-dependent exocytosis Supporting Evidence: PMID:18508778 Here, we demonstrate that syt IV itself inhibits SNARE-catalyzed membrane fusion PMID:21551071 syt IV strongly inhibited exocytosis of syt I–bearing or syt IX–bearing DCVs |
| GO:0017158 regulation of calcium ion-dependent exocytosis | IBA GO_REF:0000033 | MODIFY | Summary: IBA regulation of calcium ion-dependent exocytosis. Reason: Syt4 regulates Ca2+-dependent exocytosis, and the direction is established as negative: it inhibits SNARE-catalysed and Syt I-stimulated fusion in vitro (PMID:18508778, PMID:20688915), reduces the rate of Ca2+-induced DCV fusion in PC12 cells (PMID:20303854) and inhibits exocytosis of Syt I- and Syt IX-bearing DCVs (PMID:21551071). Refined to the negative-regulation child, which the gene carries by IDA. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000001283 SUPPORTS TRANSFER Regulation of Ca2+-dependent exocytosis holds for Syt4; the target-specific evidence fixes the sign as negative. Proposed replacements: negative regulation of calcium ion-dependent exocytosis Supporting Evidence: PMID:18508778 Here, we demonstrate that syt IV itself inhibits SNARE-catalyzed membrane fusion PMID:21551071 syt IV strongly inhibited exocytosis of syt I–bearing or syt IX–bearing DCVs |
| GO:0017158 regulation of calcium ion-dependent exocytosis | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl transfer of regulation of calcium ion-dependent exocytosis. Reason: Syt4 regulates Ca2+-dependent exocytosis, and the direction is established as negative: it inhibits SNARE-catalysed and Syt I-stimulated fusion in vitro (PMID:18508778, PMID:20688915), reduces the rate of Ca2+-induced DCV fusion in PC12 cells (PMID:20303854) and inhibits exocytosis of Syt I- and Syt IX-bearing DCVs (PMID:21551071). Refined to the negative-regulation child, which the gene carries by IDA. Proposed replacements: negative regulation of calcium ion-dependent exocytosis Supporting Evidence: PMID:20303854 Syt IV also reduced the basal rate of Ca(2+)-induced fusion. PMID:21551071 syt IV strongly inhibited exocytosis of syt I–bearing or syt IX–bearing DCVs |
| GO:0017158 regulation of calcium ion-dependent exocytosis | ISO GO_REF:0000121 | MODIFY | Summary: RGD ISO of regulation of calcium ion-dependent exocytosis. Reason: Syt4 regulates Ca2+-dependent exocytosis, and the direction is established as negative: it inhibits SNARE-catalysed and Syt I-stimulated fusion in vitro (PMID:18508778, PMID:20688915), reduces the rate of Ca2+-induced DCV fusion in PC12 cells (PMID:20303854) and inhibits exocytosis of Syt I- and Syt IX-bearing DCVs (PMID:21551071). Refined to the negative-regulation child, which the gene carries by IDA. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:101759 SUPPORTS TRANSFER Mouse IMP data (posterior pituitary, PMID:19136969) support regulation; rat data fix the sign. Proposed replacements: negative regulation of calcium ion-dependent exocytosis Supporting Evidence: PMID:20303854 Syt IV also reduced the basal rate of Ca(2+)-induced fusion. PMID:21551071 syt IV strongly inhibited exocytosis of syt I–bearing or syt IX–bearing DCVs |
| GO:0019905 syntaxin binding | IDA NOT PMID:7791877 Ca(2+)-dependent and -independent activities of neural and n... | UNDECIDED | Summary: NOT syntaxin binding (Li et al. 1995, abstract only); Syt IV C2A lacks Ca2+-dependent syntaxin binding. Reason: Abstract only. The abstract reports that the C2 domains that bind phospholipids Ca2+-dependently also bind syntaxin as a function of Ca2+, which implies that Syt IV C2A lacks Ca2+-dependent syntaxin binding. The same abstract says the cytoplasmic region of all Syts tested interacts with neural and non-neural syntaxins. Several later studies show Ca2+-independent syntaxin and t-SNARE binding by Syt IV (PMID:10397765, PMID:16618809, PMID:20688915). An unqualified NOT syntaxin binding therefore conflicts with the positive rows. Without the full text it is unclear whether the curator meant the narrower Ca2+-dependent claim. Supporting Evidence: PMID:7791877 The same C2 domains also bind syntaxin as a function of Ca2+ PMID:7791877 cytoplasmic region composed of two C2 domains that interacts with clathrin-AP2 (Kd = 0.1-1.0 nM) and with neural and non-neural syntaxins PMID:10397765 the C2A domain of Syt IV binds syntaxin isoforms in a calcium-independent manner |
| GO:0019905 syntaxin binding | IPI PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | ACCEPT | Summary: Syt IV C2A binds syntaxin-2 (P50279) Ca2+-independently. Reason: Full text read: Thomas et al. show the Syt IV C2A domain binds several syntaxin isoforms without Ca2+. Syntaxin binding is a core activity of Syt4. Supporting Evidence: PMID:10397765 the C2A domain of Syt IV binds syntaxin isoforms in a calcium-independent manner |
| GO:0019905 syntaxin binding | IPI PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | ACCEPT | Summary: Syt IV C2A binds syntaxin-4 (Q08850) Ca2+-independently. Reason: Full text read: Thomas et al. show the Syt IV C2A domain binds several syntaxin isoforms without Ca2+. Syntaxin binding is a core activity of Syt4. Supporting Evidence: PMID:10397765 the C2A domain of Syt IV binds syntaxin isoforms in a calcium-independent manner |
| GO:0019905 syntaxin binding | IPI PMID:16618809 Synaptotagmin IV is necessary for the maturation of secretor... | ACCEPT | Summary: Syt IV binds syntaxin 6, the ISG-maturation SNARE. Reason: Full text read: Syt IV binds syntaxin 6 (Q63635), a SNARE involved in ISG maturation. This links its syntaxin binding to its ISG homotypic fusion role. Supporting Evidence: PMID:16618809 Syt IV binds to syntaxin 6, a SNARE protein that is involved in ISG maturation |
| GO:0030100 regulation of endocytosis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA (ARBA plus mouse ortholog) regulation of endocytosis. Reason: Syt4 levels change endocytic kinetics: overexpression lengthens fission-pore duration and reduces endocytic vesicle size in PC12 cells (PMID:20303854), and endocytosis is accelerated in Syt4 knockout pituitary terminals (PMID:19136969). This is real but secondary to its exocytic role. Supporting Evidence: PMID:20303854 Syt IV overexpression increased the duration but not the conductance of fission pores during endocytosis. PMID:19136969 endocytosis was accelerated |
| GO:0030100 regulation of endocytosis | IMP PMID:20303854 Synaptotagmin IV modulation of vesicle size and fusion pores... | KEEP AS NON CORE | Summary: Syt IV overexpression alters fission pores and endocytic vesicle size in PC12 cells. Reason: Full text read (cell-attached capacitance; overexpression coded as IMP). Syt4 levels change endocytic kinetics: overexpression lengthens fission-pore duration and reduces endocytic vesicle size in PC12 cells (PMID:20303854), and endocytosis is accelerated in Syt4 knockout pituitary terminals (PMID:19136969). This is real but secondary to its exocytic role. Supporting Evidence: PMID:20303854 Syt IV overexpression increased the duration but not the conductance of fission pores during endocytosis. PMID:20303854 Syt IV overexpression reduced the size of DCVs and endocytotic vesicles but not MVs. |
| GO:0030100 regulation of endocytosis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of regulation of endocytosis. Reason: Syt4 levels change endocytic kinetics: overexpression lengthens fission-pore duration and reduces endocytic vesicle size in PC12 cells (PMID:20303854), and endocytosis is accelerated in Syt4 knockout pituitary terminals (PMID:19136969). This is real but secondary to its exocytic role. Supporting Evidence: PMID:19136969 endocytosis was accelerated |
| GO:0030276 clathrin binding | IDA PMID:7791877 Ca(2+)-dependent and -independent activities of neural and n... | KEEP AS NON CORE | Summary: Syt cytoplasmic domains, including Syt IV, bind clathrin-AP2 (abstract only). Reason: Abstract only: all Syts tested bind clathrin-AP2 with sub-nanomolar affinity. The binding partner is largely the AP-2 adaptor (PMID:7993622), but the curator assigned clathrin binding from the full text, and that is deferred to. It is a family-wide endocytic-adaptor interaction, not specific to Syt4 function, so non-core. Supporting Evidence: PMID:7791877 cytoplasmic region composed of two C2 domains that interacts with clathrin-AP2 (Kd = 0.1-1.0 nM) and with neural and non-neural syntaxins |
| GO:0030348 syntaxin-3 binding | IPI PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | ACCEPT | Summary: Syt IV C2A binds syntaxin-3 (Q08849). Reason: Full text read: Ca2+-independent binding of Syt IV C2A to syntaxin isoforms, including syntaxin 3. Supporting Evidence: PMID:10397765 the C2A domain of Syt IV binds syntaxin isoforms in a calcium-independent manner |
| GO:0030424 axon | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA axon (is_active_in). Reason: Syt4-bearing DCVs are transported along and captured in axons (PMID:29166604), and mouse Syt4 is found in axons by EM (PMID:12135783). The axon is a real location but transit context, not the site of a core activity beyond DCV transport, so non-core. Supporting Evidence: PMID:29166604 Kymographs of Syt4 vesicles in mid-axon and distal regions. PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0030424 axon | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of axon localisation. Reason: Syt4-bearing DCVs are transported along and captured in axons (PMID:29166604), and mouse Syt4 is found in axons by EM (PMID:12135783). The axon is a real location but transit context, not the site of a core activity beyond DCV transport, so non-core. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0030424 axon | IMP PMID:29166604 Capture of Dense Core Vesicles at Synapses by JNK-Dependent ... | KEEP AS NON CORE | Summary: Live imaging of mCherry-Syt4 DCVs in axons; location coded as IMP. Reason: Syt4-bearing DCVs are transported along and captured in axons (PMID:29166604), and mouse Syt4 is found in axons by EM (PMID:12135783). The axon is a real location but transit context, not the site of a core activity beyond DCV transport, so non-core. The axonal location rests on imaging of tagged Syt4, so IDA, not IMP, is the appropriate code. Supporting Evidence: PMID:29166604 Kymographs of Syt4 vesicles in mid-axon and distal regions. |
| GO:0030424 axon | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of axon localisation. Reason: Syt4-bearing DCVs are transported along and captured in axons (PMID:29166604), and mouse Syt4 is found in axons by EM (PMID:12135783). The axon is a real location but transit context, not the site of a core activity beyond DCV transport, so non-core. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0030425 dendrite | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of dendrite localisation. Reason: Syt4 is present in dendrites in neurons, where Syt4/BDNF vesicles undergo exocytosis (PMID:19448629, mouse) and Syt4 vesicles co-traffic with KIF1A (PMID:30021165). Non-core location. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. PMID:30021165 KIF1A-WT co-localized with NPY and Syt4 on vesicles |
| GO:0030425 dendrite | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of dendrite localisation. Reason: Syt4 is present in dendrites in neurons, where Syt4/BDNF vesicles undergo exocytosis (PMID:19448629, mouse) and Syt4 vesicles co-traffic with KIF1A (PMID:30021165). Non-core location. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. PMID:30021165 KIF1A-WT co-localized with NPY and Syt4 on vesicles |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000117 | MODIFY | Summary: ARBA cytoplasmic vesicle membrane. Reason: Correct but general. Syt4 is a single-pass protein of neuronal dense-core vesicle membranes (PMID:29166604; UniProt subcellular location). Refined to GO:0099012, already on the gene. Proposed replacements: neuronal dense core vesicle membrane Supporting Evidence: file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane PMID:29166604 Syt4 was highly co-localized with CgA |
| GO:0030667 secretory granule membrane | IDA PMID:16618809 Synaptotagmin IV is necessary for the maturation of secretor... | ACCEPT | Summary: Syt IV is localised to immature secretory granule membranes in PC12 cells. Reason: Full text read: Syt IV is on ISGs (light ISG fractions) and its cytoplasmic domain binds ISGs specifically. Combined with its TM topology, secretory granule membrane is the right location for its ISG maturation role. Supporting Evidence: PMID:16618809 We present evidence that the ISG-localized synaptotagmin IV (Syt IV) is involved in ISG maturation. PMID:16618809 Syt IV was found mainly in the light ISG-containing fractions, as well as in Golgi-containing fractions |
| GO:0031045 dense core granule | IDA PMID:10217258 Synthesis degradation, and subcellular localization of synap... | MODIFY | Summary: Syt IV in secretory granules of PC12 cells (fractionation, abstract only). Reason: Abstract supports secretory-granule localisation. Correct, but Syt4 is an integral (single-pass) membrane protein, so the membrane of the granule is the supported specific location (dense core granule membrane in PC12 cells; neuronal dense core vesicle membrane in neurons). Proposed replacements: dense core granule membrane Supporting Evidence: PMID:10217258 suggest that Syt IV protein is present in both synaptic-like microvesicles and secretory granules file:rat/Syt4/Syt4-uniprot.txt Single-pass membrane protein |
| GO:0031045 dense core granule | IDA PMID:21551071 Release mode of large and small dense-core vesicles specifie... | MODIFY | Summary: Immunogold EM puts Syt IV on PC12 DCVs. Reason: Full text: more than 50% of gold particles on DCVs. Correct, but Syt4 is an integral (single-pass) membrane protein, so the membrane of the granule is the supported specific location (dense core granule membrane in PC12 cells; neuronal dense core vesicle membrane in neurons). Proposed replacements: dense core granule membrane Supporting Evidence: PMID:21551071 For all four syt isoforms, >50% of the gold particles were on DCVs file:rat/Syt4/Syt4-uniprot.txt Single-pass membrane protein |
| GO:0031045 dense core granule | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl transfer of dense core granule. Reason: Correct, but Syt4 is an integral (single-pass) membrane protein, so the membrane of the granule is the supported specific location (dense core granule membrane in PC12 cells; neuronal dense core vesicle membrane in neurons). Proposed replacements: neuronal dense core vesicle membrane Supporting Evidence: PMID:19448629 We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane |
| GO:0031045 dense core granule | ISO GO_REF:0000121 | MODIFY | Summary: RGD ISO of dense core granule (mouse IDA, pituitary and LbetaT2 DCVs). Reason: Correct, but Syt4 is an integral (single-pass) membrane protein, so the membrane of the granule is the supported specific location (dense core granule membrane in PC12 cells; neuronal dense core vesicle membrane in neurons). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:101759 SUPPORTS TRANSFER Mouse Syt4 on DCVs of pituitary nerve terminals (PMID:19136969) and LbetaT2 cells (PMID:18468511). Proposed replacements: neuronal dense core vesicle membrane Supporting Evidence: PMID:19136969 We found Syt IV on both micro- and dense-core vesicles in posterior pituitary nerve terminals in mice. file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane |
| GO:0031338 regulation of vesicle fusion | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl transfer of regulation of vesicle fusion. Reason: Syt4 regulates vesicle fusion, with a well-established negative sign in exocytic fusion: it inhibits SNARE-catalysed fusion (PMID:18508778, PMID:20688915) and lowers the basal rate of Ca2+-induced fusion in PC12 cells (PMID:20303854). Refined to negative regulation of vesicle fusion, already on the gene by IDA. Its positive requirement for ISG homotypic fusion is captured by vesicle fusion with vesicle. Proposed replacements: negative regulation of vesicle fusion Supporting Evidence: PMID:20303854 Syt IV also reduced the basal rate of Ca(2+)-induced fusion. PMID:20688915 We report that rat SYT4 inhibited SNARE-catalyzed membrane fusion in both the absence and presence of Ca(2+). |
| GO:0031338 regulation of vesicle fusion | IMP PMID:20303854 Synaptotagmin IV modulation of vesicle size and fusion pores... | MODIFY | Summary: Syt IV overexpression reduces the basal rate of Ca2+-induced fusion and alters fusion pores in PC12 cells. Reason: Full text read. Syt4 regulates vesicle fusion, with a well-established negative sign in exocytic fusion: it inhibits SNARE-catalysed fusion (PMID:18508778, PMID:20688915) and lowers the basal rate of Ca2+-induced fusion in PC12 cells (PMID:20303854). Refined to negative regulation of vesicle fusion, already on the gene by IDA. Its positive requirement for ISG homotypic fusion is captured by vesicle fusion with vesicle. Proposed replacements: negative regulation of vesicle fusion Supporting Evidence: PMID:20303854 Syt IV also reduced the basal rate of Ca(2+)-induced fusion. |
| GO:0031338 regulation of vesicle fusion | ISO GO_REF:0000121 | MODIFY | Summary: RGD ISO of regulation of vesicle fusion. Reason: Syt4 regulates vesicle fusion, with a well-established negative sign in exocytic fusion: it inhibits SNARE-catalysed fusion (PMID:18508778, PMID:20688915) and lowers the basal rate of Ca2+-induced fusion in PC12 cells (PMID:20303854). Refined to negative regulation of vesicle fusion, already on the gene by IDA. Its positive requirement for ISG homotypic fusion is captured by vesicle fusion with vesicle. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:101759 SUPPORTS TRANSFER Mouse knockout data (PMID:19136969) support regulation of fusion; rat data fix the sign. Proposed replacements: negative regulation of vesicle fusion Supporting Evidence: PMID:20303854 Syt IV also reduced the basal rate of Ca(2+)-induced fusion. PMID:20688915 We report that rat SYT4 inhibited SNARE-catalyzed membrane fusion in both the absence and presence of Ca(2+). |
| GO:0031339 negative regulation of vesicle fusion | IDA PMID:18508778 Analysis of the synaptotagmin family during reconstituted me... | ACCEPT | Summary: Syt IV inhibits SNARE-catalysed liposome fusion and Syt I-stimulated fusion. Reason: Full text read; the core in vitro activity of this inhibitory isoform. Supporting Evidence: PMID:18508778 Here, we demonstrate that syt IV itself inhibits SNARE-catalyzed membrane fusion PMID:18508778 Thus, it appears that inhibitory isoforms of syt can impact fusion in two ways: first, they directly inhibit SNARE-mediated fusion, and second, they displace syt I from the fusion complex. |
| GO:0031339 negative regulation of vesicle fusion | IDA PMID:20688915 Rat and Drosophila synaptotagmin 4 have opposite effects dur... | ACCEPT | Summary: Rat SYT4 inhibits SNARE-catalysed fusion with or without Ca2+. Reason: Full text read; reconstituted fusion with full-length rat SYT4. Core. Supporting Evidence: PMID:20688915 We report that rat SYT4 inhibited SNARE-catalyzed membrane fusion in both the absence and presence of Ca(2+). PMID:20688915 In summary, rat SYT4 serves as an inhibitory isoform, whereas fly SYT4 is a bona fide Ca(2+) sensor capable of coupling Ca(2+) to membrane fusion. |
| GO:0031982 vesicle | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl transfer of vesicle. Reason: Correct but general: Syt4 is a membrane protein of neuronal dense-core vesicles (PMID:29166604, PMID:19448629). Refined to GO:0099012, already on the gene. Proposed replacements: neuronal dense core vesicle membrane Supporting Evidence: PMID:19448629 We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane |
| GO:0031982 vesicle | ISO GO_REF:0000121 | MODIFY | Summary: RGD ISO of vesicle. Reason: Correct but general: Syt4 is a membrane protein of neuronal dense-core vesicles (PMID:29166604, PMID:19448629). Refined to GO:0099012, already on the gene. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:101759 SUPPORTS TRANSFER Mouse Syt4 on BDNF-containing DCVs (PMID:19448629). Proposed replacements: neuronal dense core vesicle membrane Supporting Evidence: PMID:19448629 We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane |
| GO:0033604 negative regulation of catecholamine secretion | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA negative regulation of catecholamine secretion. Reason: Increased Syt IV (forskolin induction or overexpression) reduces the number of amperometric release events and the catecholamine released per PC12 cell, more strongly when Syt I is knocked down (PMID:20735850). This is a direct cell-level readout of its inhibitory role in DCV exocytosis. Supporting Evidence: PMID:20735850 These data support an inhibitory effect of syt IV on release of vesicles and their transmitter content. |
| GO:0033604 negative regulation of catecholamine secretion | IGI PMID:20735850 Upregulation of synaptotagmin IV inhibits transmitter releas... | ACCEPT | Summary: IGI with Syt1: Syt IV upregulation inhibits catecholamine release, more so after Syt I knockdown. Reason: Full text read. Increased Syt IV (forskolin induction or overexpression) reduces the number of amperometric release events and the catecholamine released per PC12 cell, more strongly when Syt I is knocked down (PMID:20735850). This is a direct cell-level readout of its inhibitory role in DCV exocytosis. Supporting Evidence: PMID:20735850 These data support an inhibitory effect of syt IV on release of vesicles and their transmitter content. |
| GO:0033604 negative regulation of catecholamine secretion | ISO GO_REF:0000121 | ACCEPT | Summary: ISO from human SYT4 (itself a transfer of this rat IGI). Reason: Increased Syt IV (forskolin induction or overexpression) reduces the number of amperometric release events and the catecholamine released per PC12 cell, more strongly when Syt I is knocked down (PMID:20735850). This is a direct cell-level readout of its inhibitory role in DCV exocytosis. The human row was made from the same rat paper, so the transfer is circular but true. Supporting Evidence: PMID:20735850 These data support an inhibitory effect of syt IV on release of vesicles and their transmitter content. |
| GO:0035773 insulin secretion involved in cellular response to glucose stimulus | IMP PMID:22939844 Reduced insulin secretion correlates with decreased expressi... | UNDECIDED | Summary: SYT4 silencing reduced glucose-stimulated insulin secretion in INS1-832/13 cells (abstract only). Reason: Abstract only. The siRNA result in a rat beta-cell line shows SYT4 is needed for full GSIS in that system, but the full text (knockdown efficiency, controls) could not be read. A positive requirement is hard to reconcile with Syt4 acting as an inhibitory isoform elsewhere. Insulin secretion involved in cellular response to glucose stimulus is a precomposed term, and whether Syt4 does work in the secretion step rather than modulating it is unresolved. Supporting Evidence: PMID:22939844 silencing of SYT4 and SYT13 reduced GSIS in INS1-832/13 cells |
| GO:0036477 somatodendritic compartment | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl transfer of somatodendritic compartment. Reason: Somatodendritic compartment is correct but general. The supported specific locations, both already on the gene, are dendrite (PMID:12135783, PMID:19448629) and neuronal cell body (PMID:15197251, PMID:12135783). Proposed replacements: dendrite neuronal cell body Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0036477 somatodendritic compartment | ISO GO_REF:0000121 | MODIFY | Summary: RGD ISO of somatodendritic compartment. Reason: Somatodendritic compartment is correct but general. The supported specific locations, both already on the gene, are dendrite (PMID:12135783, PMID:19448629) and neuronal cell body (PMID:15197251, PMID:12135783). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:101759 SUPPORTS TRANSFER Mouse EM places Syt4 in dendrites and cell body (PMID:12135783). Proposed replacements: dendrite neuronal cell body Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0042803 protein homodimerization activity | IPI PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | KEEP AS NON CORE | Summary: The Syt IV C2B domain mediates homo-oligomerisation. Reason: Full text read: the Syt IV C2B domain mediates homo-oligomerisation (reported as Ca2+-promoted, although later structural work questions C2B Ca2+ binding). This is a real biochemical property but its functional significance is not established, so non-core. The self-referencing With/From (P50232) is expected for homodimerisation. Supporting Evidence: PMID:10397765 the C2B domain of Syt IV contains calcium binding properties, which permit homo-oligomerization as well as hetero-oligomerization with Syt I |
| GO:0043005 neuron projection | IDA PMID:10646502 Synaptotagmin IV is present at the Golgi and distal parts of... | MODIFY | Summary: SytIV at distal parts of neurites in PC12 cells and hippocampal neurons. Reason: Abstract only, but it states the localisation directly. Neuron projection is correct but general. The supported specific locations, both already on the gene, are axon (PMID:29166604, PMID:12135783) and dendrite (PMID:12135783, PMID:19448629). Supporting Evidence: PMID:10646502 SytIV was localized at the Golgi and distal part of neurites in nerve growth factor-differentiated PC12 cells and cultured hippocampal neurons PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0043005 neuron projection | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl transfer of neuron projection. Reason: Neuron projection is correct but general. The supported specific locations, both already on the gene, are axon (PMID:29166604, PMID:12135783) and dendrite (PMID:12135783, PMID:19448629). Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0043005 neuron projection | ISO GO_REF:0000121 | MODIFY | Summary: RGD ISO of neuron projection. Reason: Neuron projection is correct but general. The supported specific locations, both already on the gene, are axon (PMID:29166604, PMID:12135783) and dendrite (PMID:12135783, PMID:19448629). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:101759 SUPPORTS TRANSFER Mouse neuron projection IDA (PMID:15197251); mouse EM shows axons and dendrites (PMID:12135783). Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0043025 neuronal cell body | IDA PMID:15197251 Synaptotagmin IV regulates glial glutamate release. | KEEP AS NON CORE | Summary: Syt IV immunoreactivity in hippocampal neuron cell bodies. Reason: Full text read. Syt4 is synthesised and located in neuronal cell bodies, at the Golgi (PMID:12135783, PMID:15197251). A real location, but not where its core activities act, so non-core. Supporting Evidence: PMID:15197251 Syt IV immunoreactivity was sporadically detected within neuron cell bodies in sections of hippocampus |
| GO:0043025 neuronal cell body | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined IEA neuronal cell body. Reason: Syt4 is synthesised and located in neuronal cell bodies, at the Golgi (PMID:12135783, PMID:15197251). A real location, but not where its core activities act, so non-core. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. PMID:15197251 Syt IV immunoreactivity was sporadically detected within neuron cell bodies in sections of hippocampus |
| GO:0043025 neuronal cell body | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of neuronal cell body. Reason: Syt4 is synthesised and located in neuronal cell bodies, at the Golgi (PMID:12135783, PMID:15197251). A real location, but not where its core activities act, so non-core. Supporting Evidence: PMID:12135783 In neurons of layer II/III, Syt IV was found to be localized in the dendrites and axons, and at the Golgi in the cell body. |
| GO:0044306 neuron projection terminus | IDA PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | KEEP AS NON CORE | Summary: Syt IV colocalises with Syt I at neurite tips in PC12 cells. Reason: Full text read; a location statement for neurite tips of differentiated PC12 cells. Real but non-core. Supporting Evidence: PMID:10397765 In neuroendocrine pheochromocytoma (PC12) cells, Syt IV colocalizes with Syt I in the tips of the neurites. |
| GO:0045202 synapse | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA synapse (is_active_in). Reason: Syt4 DCVs are captured at en passant presynaptic boutons (PMID:29166604), and Syt4 controls BDNF release at synapses (PMID:19448629). The synapse is a real site of Syt4 action, but it is broad and secondary to the vesicle-membrane location. Supporting Evidence: PMID:29166604 Synaptotagmin-4 (Syt4) regulates the capture and spatial distribution of DCVs in hippocampal neurons. PMID:19448629 Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. |
| GO:0045955 negative regulation of calcium ion-dependent exocytosis | IDA PMID:21551071 Release mode of large and small dense-core vesicles specifie... | ACCEPT | Summary: Syt IV inhibits exocytosis of Syt I- and Syt IX-bearing DCVs and Syt-driven liposome fusion. Reason: Full text read: forskolin induction of Syt IV inhibits exocytosis of Syt I- and Syt IX-bearing DCVs in PC12 cells, and Syt IV inhibits Syt I/VII/IX-driven liposome fusion. This is the core biological role. Supporting Evidence: PMID:21551071 syt IV strongly inhibited exocytosis of syt I–bearing or syt IX–bearing DCVs PMID:21551071 syt IV inhibited liposome fusion in the presence of each of the three other syt isoforms to the same degree |
| GO:0046929 negative regulation of neurotransmitter secretion | IDA PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | ACCEPT | Summary: Microinjected Syt IV C2A inhibits Ca2+-triggered release from PC12 cells. Reason: Full text read: the injected C2A fragment inhibits Ca2+-mediated release, reversed by alpha-latrotoxin. This is consistent with the inhibitory role seen with the full-length protein (PMID:20735850). Supporting Evidence: PMID:10397765 Microinjection of the C2A domain reveals that calcium-independent interactions mediated through this domain of Syt IV inhibit calcium-mediated neurotransmitter release from PC12 cells. PMID:20735850 These data support an inhibitory effect of syt IV on release of vesicles and their transmitter content. |
| GO:0046982 protein heterodimerization activity | IPI PMID:10397765 Functional and biochemical analysis of the C2 domains of syn... | KEEP AS NON CORE | Summary: The Syt IV C2B domain hetero-oligomerises with Syt I. Reason: Full text read: Syt IV C2B mediates hetero-oligomerisation with Syt I, also reported by Chapman et al. (PMID:9830048). This may underlie Syt IV interference with Syt I on shared vesicles, but it is not shown to be required, so non-core. Supporting Evidence: PMID:10397765 the C2B domain of Syt IV contains calcium binding properties, which permit homo-oligomerization as well as hetero-oligomerization with Syt I PMID:9830048 Ca2+ promoted the hetero-oligomerization of synaptotagmin I with synaptotagmins III and IV |
| GO:0048174 negative regulation of short-term neuronal synaptic plasticity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of negative regulation of short-term neuronal synaptic plasticity. Reason: Syt4 knockout mice show enhanced paired-pulse facilitation and post-tetanic potentiation in CA1 (PMID:15390175). Later work attributes such effects to disinhibited BDNF release (PMID:19448629), so this is an indirect, non-core role. Supporting Evidence: PMID:15390175 These results suggest Syt IV is a presynaptic negative regulator of short-term plasticity in area CA1 of the hippocampus and is required for some, but not all, forms of hippocampus-dependent memory. |
| GO:0048174 negative regulation of short-term neuronal synaptic plasticity | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of negative regulation of short-term neuronal synaptic plasticity. Reason: Syt4 knockout mice show enhanced paired-pulse facilitation and post-tetanic potentiation in CA1 (PMID:15390175). Later work attributes such effects to disinhibited BDNF release (PMID:19448629), so this is an indirect, non-core role. Supporting Evidence: PMID:15390175 These results suggest Syt IV is a presynaptic negative regulator of short-term plasticity in area CA1 of the hippocampus and is required for some, but not all, forms of hippocampus-dependent memory. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of perinuclear region of cytoplasm. Reason: Perinuclear staining reflects Syt4 accumulation at the Golgi (PMID:10646502, PMID:12135783). Real, non-core. Supporting Evidence: PMID:10646502 SytIV was localized at the Golgi and distal part of neurites in nerve growth factor-differentiated PC12 cells and cultured hippocampal neurons |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of perinuclear region of cytoplasm. Reason: Perinuclear staining reflects Syt4 accumulation at the Golgi (PMID:10646502, PMID:12135783). Real, non-core. Supporting Evidence: PMID:10646502 SytIV was localized at the Golgi and distal part of neurites in nerve growth factor-differentiated PC12 cells and cultured hippocampal neurons |
| GO:0050709 negative regulation of protein secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of negative regulation of protein secretion (BDNF). Reason: Syt4 inhibits BDNF release from hippocampal neurons (PMID:19448629, mouse), so negative regulation of protein secretion holds. The mechanistic core is captured by negative regulation of dense core granule exocytosis, so this row is kept as non-core. Supporting Evidence: PMID:19448629 syt-IV inhibited BDNF release at both sites |
| GO:0050709 negative regulation of protein secretion | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of negative regulation of protein secretion (BDNF). Reason: Syt4 inhibits BDNF release from hippocampal neurons (PMID:19448629, mouse), so negative regulation of protein secretion holds. The mechanistic core is captured by negative regulation of dense core granule exocytosis, so this row is kept as non-core. Supporting Evidence: PMID:19448629 syt-IV inhibited BDNF release at both sites |
| GO:0061782 vesicle fusion with vesicle | IMP PMID:16618809 Synaptotagmin IV is necessary for the maturation of secretor... | ACCEPT | Summary: Syt IV depletion inhibits homotypic fusion of immature secretory granules. Reason: Full text read: the Syt IV cytoplasmic domain and Syt IV siRNA both inhibit ISG homotypic fusion. Syt IV is on ISG membranes and binds the ISG SNARE syntaxin 6, so it is a participant in this fusion step. Supporting Evidence: PMID:16618809 ISG homotypic fusion was inhibited in vivo by small interfering RNA-mediated depletion of Syt IV. PMID:16618809 Syt IV binds to syntaxin 6, a SNARE protein that is involved in ISG maturation |
| GO:0061792 secretory granule maturation | IMP PMID:16618809 Synaptotagmin IV is necessary for the maturation of secretor... | ACCEPT | Summary: Syt IV is needed for maturation of secretory granules in PC12 cells. Reason: Full text read: Syt IV depletion or its cytoplasmic domain blocks ISG homotypic fusion and reduces SgII processing by PC2, while granule formation and sorting are unaffected. Supporting Evidence: PMID:16618809 We conclude that Syt IV is an essential component for secretory granule maturation. PMID:16618809 ISG homotypic fusion was inhibited in vivo by small interfering RNA-mediated depletion of Syt IV. |
| GO:0061891 calcium ion sensor activity | IBA GO_REF:0000033 | REMOVE | Summary: IBA calcium ion sensor activity from the synaptotagmin family node. Reason: Rat Syt4 has diverged from the Ca2+-sensor function of the family. Its C2A has the inactivating Asp-to-Ser (Ser244) substitution (PMID:9162066), and its C2B cannot form full Ca2+-binding sites (PMID:15311271). It does not couple Ca2+ to fusion, and inhibits fusion with or without Ca2+ (PMID:18508778, PMID:20688915). Reverting S244D restores Ca2+-sensor function, which pins the loss to the substitution. Dai et al. state explicitly that Syt4 is a Ca2+ sensor in the fly but not in the rat. This is an over-propagated IBA argued against on target-specific grounds. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN000001283 SUPPORTS SOURCE BUT NOT TARGET Ca2+-sensor activity is seeded by Syt1/Syt2-type isoforms and invertebrate orthologs; the mammalian Syt4/Syt11 subclade has lost it. RGD:3803 SUPPORTS SOURCE BUT NOT TARGET Syt1 is a bona fide Ca2+ sensor; this does not transfer to rat Syt4. Supporting Evidence: PMID:15311271 These results indicate that synaptotagmin 4 is a Ca(2+) sensor in the fly but not in the rat PMID:20688915 In summary, rat SYT4 serves as an inhibitory isoform, whereas fly SYT4 is a bona fide Ca(2+) sensor capable of coupling Ca(2+) to membrane fusion. PMID:20688915 Rat SYT4 was able to stimulate fusion in response to Ca(2+) when the conserved Asp-to-Ser Ca(2+) ligand substitution in its C2A domain was reversed. file:rat/Syt4/Syt4-uniprot.txt Synaptotagmin family member which does not bind Ca(2+) |
| GO:0070382 exocytic vesicle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA exocytic vesicle (is_active_in). Reason: Syt IV is transported to secretory vesicles (PMID:10217258) and sits on DCVs and ISGs that undergo regulated exocytosis (PMID:21551071, PMID:19448629). Exocytic vesicle is correct and the supporting evidence comes from neuroendocrine vesicles. GO does not place dense core granule under exocytic vesicle, so this row is not redundant with the DCV terms, but the DCV membrane term is the core location. Supporting Evidence: PMID:10217258 is rapidly transported to secretory vesicles where it may transiently modulate the exocytotic machinery |
| GO:0070382 exocytic vesicle | IDA PMID:10217258 Synthesis degradation, and subcellular localization of synap... | KEEP AS NON CORE | Summary: Syt IV on PC12 secretory vesicles, co-isolated with Syt I (abstract only). Reason: Abstract states vesicle co-isolation with Syt I. Syt IV is transported to secretory vesicles (PMID:10217258) and sits on DCVs and ISGs that undergo regulated exocytosis (PMID:21551071, PMID:19448629). Exocytic vesicle is correct and the supporting evidence comes from neuroendocrine vesicles. GO does not place dense core granule under exocytic vesicle, so this row is not redundant with the DCV terms, but the DCV membrane term is the core location. Supporting Evidence: PMID:10217258 is rapidly transported to secretory vesicles where it may transiently modulate the exocytotic machinery |
| GO:0097449 astrocyte projection | IDA PMID:15197251 Synaptotagmin IV regulates glial glutamate release. | KEEP AS NON CORE | Summary: Syt IV in astroglial processes in situ. Reason: Full text read. Syt IV is in astrocyte processes in situ and supports Ca2+-dependent glutamate release from astrocytes (PMID:15197251). Real, cell-type-specific location, non-core. Supporting Evidence: PMID:15197251 we find that Syt IV is located in processes of astroglia in situ |
| GO:0097449 astrocyte projection | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of astrocyte projection. Reason: Syt IV is in astrocyte processes in situ and supports Ca2+-dependent glutamate release from astrocytes (PMID:15197251). Real, cell-type-specific location, non-core. Supporting Evidence: PMID:15197251 we find that Syt IV is located in processes of astroglia in situ |
| GO:0097449 astrocyte projection | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of astrocyte projection. Reason: Syt IV is in astrocyte processes in situ and supports Ca2+-dependent glutamate release from astrocytes (PMID:15197251). Real, cell-type-specific location, non-core. Supporting Evidence: PMID:15197251 we find that Syt IV is located in processes of astroglia in situ |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of glutamatergic synapse. Reason: Mouse Syt4 acts at glutamatergic hippocampal synapses, controlling BDNF release that modulates presynaptic release and LTP (PMID:19448629). Real but a synapse-level context, non-core. Supporting Evidence: PMID:19448629 Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of glutamatergic synapse. Reason: Mouse Syt4 acts at glutamatergic hippocampal synapses, controlling BDNF release that modulates presynaptic release and LTP (PMID:19448629). Real but a synapse-level context, non-core. Supporting Evidence: PMID:19448629 Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. |
| GO:0098992 neuronal dense core vesicle | IDA PMID:29166604 Capture of Dense Core Vesicles at Synapses by JNK-Dependent ... | MODIFY | Summary: Syt4 colocalises with chromogranin A on DCVs in hippocampal neurons. Reason: Full text read: Syt4 is highly colocalised with the DCV marker CgA. As an integral membrane protein, Syt4 is on the DCV membrane, the more specific location already carried by the gene (GO:0099012). Proposed replacements: neuronal dense core vesicle membrane Supporting Evidence: PMID:29166604 Syt4 was highly co-localized with CgA file:rat/Syt4/Syt4-uniprot.txt Single-pass membrane protein |
| GO:0099012 neuronal dense core vesicle membrane | IDA PMID:30021165 Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca(... | ACCEPT | Summary: Syt4 is an integral membrane protein of neuronal DCVs that binds KIF1A. Reason: Full text read: Syt4 is described as an integral DCV membrane protein and co-traffics with KIF1A on DCVs. Core location. Supporting Evidence: PMID:30021165 The integral membrane protein synaptotagmin 4 (Syt4) is also present on DCVs PMID:30021165 KIF1A-WT co-localized with NPY and Syt4 on vesicles |
| GO:0099012 neuronal dense core vesicle membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA neuronal dense core vesicle membrane (UniProt subcellular location). Reason: Matches the curated UniProt subcellular location backed by PMID:29166604. Core location. Supporting Evidence: file:rat/Syt4/Syt4-uniprot.txt Cytoplasmic vesicle, secretory vesicle, neuronal dense core vesicle membrane PMID:29166604 Syt4 was highly co-localized with CgA |
| GO:0099012 neuronal dense core vesicle membrane | ISO GO_REF:0000121 | ACCEPT | Summary: RGD ISO of neuronal dense core vesicle membrane (is_active_in). Reason: Mouse Syt4 is on BDNF-containing DCVs (PMID:19448629) and pituitary DCVs (PMID:19136969), and rat Syt4 is shown there directly. Core location. Supporting Evidence: PMID:19448629 We found that syt-IV localized to brain-derived neurotrophic factor (BDNF)-containing vesicles in hippocampal neurons. PMID:29166604 Syt4 was highly co-localized with CgA |
| GO:0099502 calcium-dependent activation of synaptic vesicle fusion | IBA GO_REF:0000033 | REMOVE | Summary: IBA calcium-dependent activation of synaptic vesicle fusion. Reason: Rat Syt4 cannot couple Ca2+ to fusion and inhibits fusion (PMID:20688915, PMID:18508778). It is also not a synaptic vesicle protein in neurons (PMID:12135783, PMID:15197251). The node was seeded by a Ca2+-sensing isoform; the term is wrong for the target on both function and location. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN004120656 SUPPORTS SOURCE BUT NOT TARGET Seeded by MGI:1859545 (a Ca2+-sensing synaptotagmin); rat Syt4 is Ca2+-insensitive, inhibitory and absent from synaptic vesicles. Supporting Evidence: PMID:20688915 In summary, rat SYT4 serves as an inhibitory isoform, whereas fly SYT4 is a bona fide Ca(2+) sensor capable of coupling Ca(2+) to membrane fusion. PMID:12135783 EM and cell fractionation studies showed no Syt IV signals at synaptic vesicles |
| GO:0099519 dense core granule cytoskeletal transport | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfer of dense core granule cytoskeletal transport. Reason: Syt4 links DCVs to the kinesin KIF1A: KIF1A knockdown reduces Syt4 DCV numbers and mobility in axons, and JNK phosphorylation of Syt4 Ser135 weakens Syt4-KIF1A binding, switching DCVs from microtubule transport to capture at synapses (PMID:29166604). Syt4 does work in this process as the vesicle-side KIF1A attachment whose phosphorylation state controls transport. Core. Supporting Evidence: PMID:29166604 Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction PMID:29166604 indicating that Kif1A is the motor protein that transports Syt4-harboring DCVs |
| GO:0099519 dense core granule cytoskeletal transport | IMP PMID:29166604 Capture of Dense Core Vesicles at Synapses by JNK-Dependent ... | ACCEPT | Summary: Syt4 phospho-mutants alter axonal DCV mobility via the Syt4-KIF1A interaction. Reason: Full text read. Syt4 links DCVs to the kinesin KIF1A: KIF1A knockdown reduces Syt4 DCV numbers and mobility in axons, and JNK phosphorylation of Syt4 Ser135 weakens Syt4-KIF1A binding, switching DCVs from microtubule transport to capture at synapses (PMID:29166604). Syt4 does work in this process as the vesicle-side KIF1A attachment whose phosphorylation state controls transport. Core. Supporting Evidence: PMID:29166604 Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction PMID:29166604 indicating that Kif1A is the motor protein that transports Syt4-harboring DCVs |
| GO:0099519 dense core granule cytoskeletal transport | ISO GO_REF:0000121 | ACCEPT | Summary: RGD ISO of dense core granule cytoskeletal transport. Reason: Syt4 links DCVs to the kinesin KIF1A: KIF1A knockdown reduces Syt4 DCV numbers and mobility in axons, and JNK phosphorylation of Syt4 Ser135 weakens Syt4-KIF1A binding, switching DCVs from microtubule transport to capture at synapses (PMID:29166604). Syt4 does work in this process as the vesicle-side KIF1A attachment whose phosphorylation state controls transport. Core. Supporting Evidence: PMID:29166604 Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction |
| GO:0150035 regulation of trans-synaptic signaling by BDNF, modulating synaptic transmission | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of regulation of trans-synaptic signaling by BDNF. Reason: Mouse postsynaptic Syt4 regulates BDNF release and thereby the trans-synaptic action of BDNF on presynaptic release (PMID:19448629). Real, but a downstream consequence of its DCV-exocytosis role, so non-core. Supporting Evidence: PMID:19448629 Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. |
| GO:0150035 regulation of trans-synaptic signaling by BDNF, modulating synaptic transmission | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of regulation of trans-synaptic signaling by BDNF. Reason: Mouse postsynaptic Syt4 regulates BDNF release and thereby the trans-synaptic action of BDNF on presynaptic release (PMID:19448629). Real, but a downstream consequence of its DCV-exocytosis role, so non-core. Supporting Evidence: PMID:19448629 Thus, postsynaptic syt-IV regulates the trans-synaptic action of BDNF to control presynaptic vesicle dynamics. |
| GO:0150044 regulation of postsynaptic dense core vesicle exocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of regulation of postsynaptic dense core vesicle exocytosis. Reason: Syt4 inhibits BDNF release from dendrites as well as axons (PMID:19448629). GO has no negative-regulation child of this term, so it is as precise as available. Non-core: a neuron-compartment-specific instance of the core DCV-exocytosis inhibition. Supporting Evidence: PMID:19448629 syt-IV inhibited BDNF release at both sites |
| GO:0150044 regulation of postsynaptic dense core vesicle exocytosis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of regulation of postsynaptic dense core vesicle exocytosis. Reason: Syt4 inhibits BDNF release from dendrites as well as axons (PMID:19448629). GO has no negative-regulation child of this term, so it is as precise as available. Non-core: a neuron-compartment-specific instance of the core DCV-exocytosis inhibition. Supporting Evidence: PMID:19448629 syt-IV inhibited BDNF release at both sites |
| GO:1903861 positive regulation of dendrite extension | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: ISO from human SYT4 positive regulation of dendrite extension (UniProt IDA, PMID:23999003, melanocyte dendrites). Reason: The human donor comes from an overexpression screen in mouse melan-a melanocytes, where C2-domain proteins lengthened melanocyte dendrites; the abstract focuses on SYT14L. GO dendrite extension refers to neuronal dendrites ("growth of a single dendrite"; GO dendrite is a neuron projection), not melanocyte processes. Overexpression-induced process lengthening in a pigment cell line is weak evidence for a neuronal developmental role of Syt4, and no rat or neuronal study supports it. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: CONTEXT OR TISSUE MISMATCH SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q9H2B2 SOURCE WEAK OR INFERRED Human IDA (PMID:23999003) from melanocyte overexpression; the term is neuronal dendrite extension. Supporting Evidence: PMID:23999003 Sixteen sets of C2 domain-containing proteins were identified whose over-expression resulted in dendrite lengthening. PMID:23999003 we focused on the C2 domain of SYT14L |
| GO:1905414 negative regulation of dense core granule exocytosis | IMP PMID:20303854 Synaptotagmin IV modulation of vesicle size and fusion pores... | ACCEPT | Summary: Syt IV overexpression lowers the rate of Ca2+-induced DCV fusion in PC12 cells. Reason: Full text read: overexpressed Syt IV reduces the basal rate of Ca2+-induced fusion and DCV size. The core inhibitory role of Syt4 on DCV exocytosis (also PMID:21551071, PMID:20735850). Supporting Evidence: PMID:20303854 Syt IV also reduced the basal rate of Ca(2+)-induced fusion. |
| GO:1905415 positive regulation of dense core granule exocytosis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of positive regulation of dense core granule exocytosis. Reason: Mouse/LbetaT2 knockdown reduced Ca2+-triggered DCV exocytosis (PMID:18468511), and in pituitary terminals Syt4 loss raises exocytosis at low Ca2+ but lowers it at high Ca2+ (PMID:19136969). So Syt4 can support DCV exocytosis in some settings, although its dominant, biochemically explained role is inhibitory. Kept as a non-core, context-dependent role. Supporting Evidence: PMID:18468511 Downregulation of Syt IV clearly reduced Ca(2+)-triggered exocytosis of dense core vesicles (DCVs) in LbetaT2 cells. PMID:19136969 low Ca(2+) entry triggered more exocytosis, high Ca(2+) entry triggered less exocytosis |
| GO:1905415 positive regulation of dense core granule exocytosis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of positive regulation of dense core granule exocytosis. Reason: Mouse/LbetaT2 knockdown reduced Ca2+-triggered DCV exocytosis (PMID:18468511), and in pituitary terminals Syt4 loss raises exocytosis at low Ca2+ but lowers it at high Ca2+ (PMID:19136969). So Syt4 can support DCV exocytosis in some settings, although its dominant, biochemically explained role is inhibitory. Kept as a non-core, context-dependent role. Supporting Evidence: PMID:18468511 Downregulation of Syt IV clearly reduced Ca(2+)-triggered exocytosis of dense core vesicles (DCVs) in LbetaT2 cells. PMID:19136969 low Ca(2+) entry triggered more exocytosis, high Ca(2+) entry triggered less exocytosis |
| GO:1905433 negative regulation of retrograde trans-synaptic signaling by neuropeptide | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfer of negative regulation of retrograde trans-synaptic signaling by neuropeptide. Reason: Postsynaptic Syt4 inhibits BDNF release, which acts retrogradely on presynaptic terminals (PMID:19448629). Real, downstream of the core DCV role, non-core. Supporting Evidence: PMID:19448629 Knockout of syt-IV increased, and overexpression decreased, the rate of synaptic vesicle exocytosis from presynaptic terminals indirectly via changes in postsynaptic release of BDNF. |
| GO:1905433 negative regulation of retrograde trans-synaptic signaling by neuropeptide | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: RGD ISO of negative regulation of retrograde trans-synaptic signaling by neuropeptide. Reason: Postsynaptic Syt4 inhibits BDNF release, which acts retrogradely on presynaptic terminals (PMID:19448629). Real, downstream of the core DCV role, non-core. Supporting Evidence: PMID:19448629 Knockout of syt-IV increased, and overexpression decreased, the rate of synaptic vesicle exocytosis from presynaptic terminals indirectly via changes in postsynaptic release of BDNF. |
| GO:1990742 microvesicle | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl transfer of mouse microvesicle (extracellular vesicle). Reason: GO:1990742 microvesicle is an extracellular vesicle shed from the plasma membrane. The mouse donor (ARUK-UCL IDA, PMID:19136969) uses "microvesicles" for intracellular synaptic-like microvesicles in posterior pituitary nerve terminals, so the term is a mistranslation of the paper. No evidence places Syt4 in shed extracellular vesicles. Supporting Evidence: PMID:19136969 We found Syt IV on both micro- and dense-core vesicles in posterior pituitary nerve terminals in mice. |
| GO:1990742 microvesicle | ISO GO_REF:0000121 | REMOVE | Summary: RGD ISO of mouse microvesicle (extracellular vesicle). Reason: GO:1990742 microvesicle is an extracellular vesicle shed from the plasma membrane. The mouse donor (ARUK-UCL IDA, PMID:19136969) uses "microvesicles" for intracellular synaptic-like microvesicles in posterior pituitary nerve terminals, so the term is a mistranslation of the paper. No evidence places Syt4 in shed extracellular vesicles. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: MGI:MGI:101759 SOURCE BAD Mouse IDA (PMID:19136969) uses GO microvesicle (extracellular) for intracellular synaptic-like microvesicles. Supporting Evidence: PMID:19136969 We found Syt IV on both micro- and dense-core vesicles in posterior pituitary nerve terminals in mice. |
| GO:2000301 negative regulation of synaptic vesicle exocytosis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl transfer of negative regulation of synaptic vesicle exocytosis. Reason: Dean et al. show that Syt4 knockout increases and overexpression decreases presynaptic synaptic vesicle exocytosis indirectly, through changes in postsynaptic BDNF release (PMID:19448629). Syt4 is not on synaptic vesicles (PMID:12135783), so it does no work in synaptic vesicle exocytosis and the effect is an indirect downstream consequence. Supporting Evidence: PMID:19448629 Knockout of syt-IV increased, and overexpression decreased, the rate of synaptic vesicle exocytosis from presynaptic terminals indirectly via changes in postsynaptic release of BDNF. PMID:12135783 EM and cell fractionation studies showed no Syt IV signals at synaptic vesicles |
| GO:2000301 negative regulation of synaptic vesicle exocytosis | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: RGD ISO of negative regulation of synaptic vesicle exocytosis. Reason: Dean et al. show that Syt4 knockout increases and overexpression decreases presynaptic synaptic vesicle exocytosis indirectly, through changes in postsynaptic BDNF release (PMID:19448629). Syt4 is not on synaptic vesicles (PMID:12135783), so it does no work in synaptic vesicle exocytosis and the effect is an indirect downstream consequence. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:101759 SOURCE WEAK OR INFERRED Mouse IMP (PMID:19448629); the paper states the effect on presynaptic SV exocytosis is indirect via BDNF. Supporting Evidence: PMID:19448629 Knockout of syt-IV increased, and overexpression decreased, the rate of synaptic vesicle exocytosis from presynaptic terminals indirectly via changes in postsynaptic release of BDNF. |
| GO:0019894 kinesin binding | IPI PMID:29166604 Capture of Dense Core Vesicles at Synapses by JNK-Dependent ... | NEW | Summary: Proposed new molecular function: Syt4 binds the kinesin-3 motor KIF1A, regulated by JNK phosphorylation at Ser135 and by Ca2+. Reason: Bharat et al. show a direct Syt4-KIF1A interaction that is weakened by phosphomimetic S135E and strengthened by S135A, and that KIF1A transports Syt4 DCVs. Stucchi et al. independently find Syt4 among Ca2+-dependent KIF1A interactors and pull down mCherry-Syt4 with a KIF1A tail fragment. This is the molecular basis of the accepted DCV cytoskeletal transport role and replaces the bare protein-binding row (PMID:29166604). It is a molecular function, so the process-term bar does not apply, and it is not an ancestor or descendant of any other term on the gene. Supporting Evidence: PMID:29166604 Phosphorylation of serine 135 of Syt4 by JNK steers DCV trafficking by destabilizing Syt4-Kif1A interaction PMID:30021165 Only in the presence of calcium KIF1A(657-1698) associated with specific DCV-related proteins such as Syt4 and synaptotagmin 11 (Syt11) file:rat/Syt4/Syt4-uniprot.txt Involved in neuronal dense core vesicles (DCVs) mobility through its interaction with KIF1A. |
Loading supporting content…
Download this section (compressed HTML)Q: Does the Ca2+-independent PS binding of rat Syt4 seen in co-flotation (PMID:18508778), but not in co-sedimentation (PMID:20688915), occur on native membranes, and does it contribute to inhibition of fusion?
Q: Should NOT syntaxin binding (PMID:7791877) be restricted to Ca2+-dependent binding, given the Ca2+-independent syntaxin binding of Syt4 shown in later work?
Q: How does Syt4 support glucose-stimulated insulin secretion in beta-cell lines (PMID:22939844) while acting as an inhibitory isoform in PC12 cells and neurons?
Experiment: Map the KIF1A-binding surface on Syt4 and test whether it overlaps the t-SNARE-binding surface, using purified proteins with S135A/S135E phosphomutants in direct binding assays.
Experiment: Compare wild-type and S244D Syt4 knock-in neurons for BDNF release and axonal DCV capture to separate the effects of the inhibitory, Ca2+-insensitive C2A from those of KIF1A binding.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)