Affinage

SYT5

Synaptotagmin-5 · UniProt O00445

Length
386 aa
Mass
42.9 kDa
Annotated
2026-06-10
23 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYT5 (synaptotagmin 5) is a Ca2+-sensing protein that couples Ca2+ signals to membrane fusion in multiple regulated secretion and organelle-fusion contexts (PMID:30659119, PMID:40413756). In endothelial cells it localizes to Weibel-Palade bodies and acts as the Ca2+ sensor for histamine-evoked, Ca2+-dependent exocytosis of von Willebrand factor, with Ca2+ binding through residue Asp197 being essential — a Ca2+-binding-defective Asp197Ser mutant phenocopies SYT5 depletion (PMID:30659119). SYT5 also serves as the Ca2+ sensor for autophagosome-lysosome fusion, operating downstream of the MCOLN1/MCOLN3 heteromeric Ca2+ channel and PtdIns4P; coincident binding of both Ca2+ and PtdIns4P to SYT5 is required to assemble the fusion complex that drives this step (PMID:40413756). The human gene resides on chromosome 19q13.4 adjacent to SYT3 and is alternatively spliced (PMID:9177789). Beyond these fusion roles, the molecular details of SYT5's fusion partners and structural mechanism have not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 1997 Medium

    Established the human SYT5 gene's coding sequence, chromosomal location, and intron-exon organization, defining it as a member of a linked synaptotagmin gene cluster and providing the molecular foundation for functional study.

    Evidence cDNA sequencing, genomic structure determination, and chromosomal mapping by PCR and hybridization to chromosome 19 cosmids

    PMID:9177789

    Open questions at the time
    • No functional or localization data for the protein
    • Significance of alternative splicing not resolved
    • No Ca2+-binding or fusion activity demonstrated
  2. 2019 High

    Resolved whether SYT5 acts as a functional Ca2+ sensor in regulated exocytosis by showing it controls Ca2+-dependent Weibel-Palade body exocytosis and VWF secretion in endothelial cells.

    Evidence shRNA knockdown, overexpression, Asp197Ser Ca2+-binding mutant, and live-cell exocytosis/VWFpp secretion assays in HUVECs

    PMID:30659119

    Open questions at the time
    • Fusion machinery partners of SYT5 at the WPB not identified
    • Structural basis of Ca2+ sensing beyond Asp197 not defined
    • Single lab
  3. 2020 Medium

    Extended SYT5's Ca2+-sensor role to neuronal-type vesicle recycling and indicated it can be functionally impaired by cross-reactive antibodies, hinting at an autoimmune-mimicry vulnerability.

    Evidence Antibody perturbation (anti-H. pylori cross-reactive and SYT5-specific), Ca2+ imaging, and vesicle recycling assays in SiMa neuroblastoma cells

    PMID:32860155

    Open questions at the time
    • Indirect antibody-based perturbation rather than genetic loss-of-function
    • Molecular epitope and mechanism of impairment undefined
    • Physiological relevance of the mimicry in vivo unknown
  4. 2025 High

    Defined SYT5 as the Ca2+ sensor for autophagosome-lysosome fusion, placing it in a discrete signaling axis where it decodes local Ca2+ and lipid cues to drive organelle fusion.

    Evidence KO and dominant-negative approaches for MCOLN1/MCOLN3/SYT5, Ca2+ imaging, PtdIns4P manipulation, mRFP-GFP-LC3 flux assays, co-IP, and epistasis analysis

    PMID:40413756

    Open questions at the time
    • Identity of the SYT5-containing fusion complex components not fully defined
    • Structural basis of dual Ca2+/PtdIns4P binding not resolved
    • Single lab
  5. 2025 Low

    Associated SYT5 upregulation with a brain-repair protein network following neonatal hypoxic-ischemic injury, raising a possible role in injury response.

    Evidence Proteomic profiling and bioinformatic protein-protein interaction analysis in a neonatal rat HI brain injury model

    PMID:40533307

    Open questions at the time
    • Interactions are bioinformatic inference, not experimentally validated
    • No direct functional role for SYT5 in brain repair demonstrated
    • Proteomic upregulation lacks mechanistic follow-up

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown which SNARE or core fusion-machinery partners SYT5 engages at each membrane and what structural features confer its dual Ca2+/lipid coincidence detection.
  • No structural model of SYT5 C2 domains in the corpus
  • Direct fusion-machinery partners unidentified
  • Whether the WPB and autophagosome roles share mechanism is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140299 molecular sensor activity 2 GO:0008289 lipid binding 1
Localization
GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9612973 Autophagy 1
Partners
MCOLN1MCOLN3

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 SYT5 localizes to Weibel-Palade bodies (WPBs) in human endothelial cells and acts as a Ca2+ sensor regulating Ca2+-dependent WPB exocytosis. shRNA knockdown of SYT5 reduced histamine-evoked WPB exocytosis and VWF-propeptide secretion; overexpression increased both. A Ca2+-binding defective mutant (Asp197Ser) mimicked SYT5 depletion, establishing Ca2+ binding as essential for function. shRNA knockdown, overexpression of SYT5-mEGFP/mCherry, Ca2+-binding defective mutant (Asp197Ser), live-cell exocytosis assays, Western blot, VWFpp secretion assay in HUVECs Journal of cell science High 30659119
2025 SYT5 functions as the Ca2+ sensor for autophagosome-lysosome fusion, acting downstream of the MCOLN1/TRPML1-MCOLN3/TRPML3 heteromeric Ca2+ channel and PtdIns4P. Ca2+ released from autophagosomes via this channel is decoded by SYT5; binding of both Ca2+ and PtdIns4P to SYT5 is required for forming the fusion complex that drives autophagosome-lysosome fusion. Knockout and dominant-negative approaches for MCOLN1, MCOLN3, SYT5; Ca2+ imaging; PtdIns4P manipulation; autophagy flux assays (mRFP-GFP tandem LC3); co-immunoprecipitation; epistasis analysis Autophagy High 40413756
1997 Human SYT5 (SYTV) encodes a 386-amino-acid protein that is 91% identical to rat Syt V, and its gene is located on chromosome 19q13.4 very close to SYTIII, with seven introns that can be alternatively spliced, establishing linked synaptotagmin genes. cDNA sequencing, genomic structure determination, PCR of somatic cell hybrids, DNA hybridization to chromosome 19 cosmid array Genomics Medium 9177789
2020 Antibodies cross-reactive between Helicobacter pylori antigens and SYT5 (molecular mimicry) impair SYT5 function in SiMa neuroblastoma cells, as demonstrated by significant reduction of acetylcholine-dependent Ca2+ signals and vesicle recycling, mimicking the effect of SYT5-specific antibodies. This positions SYT5 as a functional Ca2+ sensor for vesicle recycling in neuroblastoma cells. Immunofluorescence, Western blot, multiprotein array, Ca2+ imaging, vesicle recycling assay in SiMa cells pretreated with anti-HPy antibodies or SYT5-specific antibodies Journal of molecular neuroscience : MN Medium 32860155
2025 In a neonatal rat HI brain injury model treated with BRT_002, proteomic analysis identified upregulation of Syt5, and protein-protein interaction analysis suggested Syt5 interacts with Fblim1 (which connects to Agrin, Zyxin, Vegfa, Vwf, and mitochondrial targets), implicating SYT5 in a network associated with brain repair. Proteomic analysis of brain tissue, bioinformatics protein-protein interaction analysis Neurotherapeutics Low 40533307

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum-plasma membrane contact sites consisting of three synaptotagmins. The New phytologist 48 31869440
2019 Genome-Wide Plasma Cell-Free DNA Methylation Profiling Identifies Potential Biomarkers for Lung Cancer. Disease markers 43 30867848
2020 LCM-seq reveals unique transcriptional adaptation mechanisms of resistant neurons and identifies protective pathways in spinal muscular atrophy. Genome research 36 32820007
2020 Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets. Endocrinology 30 32894758
2014 Human enteroendocrine cell responses to infection with Chlamydia trachomatis: a microarray study. Gut pathogens 22 24959205
2019 Synaptotagmin 5 regulates Ca2+-dependent Weibel-Palade body exocytosis in human endothelial cells. Journal of cell science 19 30659119
2010 Developmental expression of Synaptotagmin isoforms in single calyx of Held-generating neurons. Molecular and cellular neurosciences 19 20470891
2009 Spatial differences in molecular characteristics of the pontine parabrachial nucleus. Brain research 12 19664607
2023 Genome-Wide Re-Sequencing Data Reveals the Population Structure and Selection Signatures of Tunchang Pigs in China. Animals : an open access journal from MDPI 11 37889708
2020 A machine learning analysis of a "normal-like" IDH-WT diffuse glioma transcriptomic subgroup associated with prolonged survival reveals novel immune and neurotransmitter-related actionable targets. BMC medicine 11 33059718
2016 Expressions of SH3BP5, LMO3, and SNAP25 in diffuse large B-cell lymphoma cells and their association with clinical features. Cancer medicine 11 27184832
2021 Expression and distribution of synaptotagmin family members in the zebrafish retina. The Journal of comparative neurology 10 34468021
1997 Human synaptotagmin V (SYT5): sequence, genomic structure, and chromosomal location. Genomics 8 9177789
2024 Unraveling the significance of PPP1R1A gene in pancreatic β-cell function: A study in INS-1 cells and human pancreatic islets. Life sciences 5 38574885
2008 Genes on bovine chromosome 18 associated with bilateral convergent strabismus with exophthalmos in German Brown cattle. Molecular vision 5 18836565
2012 PLXNC1 and RDH13 associated with bilateral convergent strabismus with exophthalmus in German Brown cattle. Molecular vision 4 22933835
2025 Autoantibodies towards HFE and SYT5 in anti-neutrophil cytoplasm antibody-associated vasculitis relapse. Rheumatology (Oxford, England) 3 39400561
2024 Discovery and Validation of Survival-Specific Genes in Papillary Renal Cell Carcinoma Using a Customized Next-Generation Sequencing Gene Panel. Cancers 3 38893126
2023 Expression Silencing of Mitogen-Activated Protein Kinase 8 Interacting Protein-1 Conferred Its Role in Pancreatic β-Cell Physiology and Insulin Secretion. Metabolites 2 36837926
2020 Interactions of Antibodies to the Gram-Negative Gastric Bacterium Helicobacter pylori with the Synaptic Calcium Sensor Synaptotagmin 5, Correlate to Impaired Vesicle Recycling in SiMa Human Neuroblastoma Cells. Journal of molecular neuroscience : MN 2 32860155
2025 Novel purine derivatives mitigate hypoxia ischemia related brain injury through agrin, zyxin and synaptotagmin proteins. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 1 40533307
2025 MCOLN1/TRPML1-MCOLN3/TRPML3 heteromer and its coupling to Ca2+ sensor SYT5 regulates autophagosome-lysosome fusion in a PtdIns4P-dependent manner. Autophagy 0 40413756
2025 Impact of PPP1R1A Knockdown on the Proteomic Landscape of INS-1 Cells: A Focus on Significant Modulated Pathways. Journal of proteome research 0 41359828

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