Syt3 (rat, P40748) — manual literature synthesis

No deep-research provider was available for this session; this synthesis was written by the
reviewer from cached publications (publications/PMID_*.md) and PubMed searches.

Identity and architecture

• Synaptotagmin-3, 588 aa, single-pass membrane protein with a short N-terminal intravesicular/extracellular
  segment carrying a cysteine motif, a TM helix (55-75), a linker and tandem C2 domains (C2A 297-418, C2B 429-563)
  [UniProtKB:P40748 "Belongs to the synaptotagmin family"].
• Homodimerizes through disulfides in the cysteine motif and heterodimerizes with SYT6, SYT9, SYT10
  [UniProtKB:P40748 "Homodimer; disulfide-linked via the cysteine motif"]. Ca2+ promotes C2B-mediated
  hetero-oligomerization with Syt1 PMID:9830048.

Biochemistry: a high-affinity Ca2+ sensor

• Binds 3 Ca2+ per subunit on the C2 domains [UniProtKB:P40748 "Binds 3 Ca(2+) ions per subunit"].
• C2A binds phospholipids Ca2+-dependently PMID:7791877;
  Syt3 has one of the highest apparent Ca2+ affinities in the family
  PMID:11823420.
• Ca2+-promoted binding to syntaxin-1A/SNAP-25 t-SNARE heterodimers PMID:12860971;
  binds PS-containing liposomes and PIP2 PMID:12860971.
• Cytoplasmic domain of Syt3 stimulates SNARE-catalysed liposome fusion in response to Ca2+
  PMID:18508778.
• Binds clathrin-AP2 and syntaxins via the cytoplasmic region PMID:7791877.

Localization

• Enriched in synaptic plasma membranes, not synaptic vesicles PMID:10373432.
• Plasma membrane in PC12 cells PMID:11823420.
• Postsynaptic endocytic zones PMID:30545844; multivesicular bodies in T cells PMID:17179206.

Physiological roles

• Postsynaptic: Ca2+-sensing by Syt3 drives AMPA receptor (GluA2) internalization, LTD, LTP decay and forgetting
  PMID:30545844. Syt3-GluA2 binding also implicated in ischemic damage PMID:36892998.
• Presynaptic: high-affinity Ca2+ sensor for synaptic vesicle replenishment and short-term plasticity
  PMID:36261524.
• Endocrine/PC12: proposed plasma-membrane Ca2+ sensor for exocytosis (C2A interference) PMID:11823420.
• T cells: CXCR4 recycling PMID:17179206.
• Melanocyte dendrite claim (human SYT3, UniProt IDA from PMID:23999003) rests on a C2-domain overexpression screen focused on SYT14L.