Synaptophysin (SYP) GO Annotation Review Summary

Gene: SYP (Synaptophysin)
UniProt ID: P08247
Organism: Homo sapiens
Review Date: 2025-11-16
Total Annotations Reviewed: 38

Overview

Synaptophysin is a major integral membrane protein of synaptic vesicles with four transmembrane domains (MARVEL domain). It regulates synaptic vesicle endocytosis kinetics, interacts with synaptobrevin-2/VAMP2, binds cholesterol for vesicle biogenesis, and modulates synaptic plasticity. Forms hexameric structures and acts as a membrane elastomer regulating vesicle size and neurotransmitter-dependent expansion.

Curation Action Summary

Action Count Percentage Description
ACCEPT 29 76.3% Annotations accepted as core or valid functions
KEEP_AS_NON_CORE 3 7.9% Correct but peripheral annotations
MODIFY 1 2.6% Annotations requiring more specific terms
REMOVE 5 13.2% Annotations to be removed
TOTAL 38 100%

Key Findings

Core Functions Confirmed

  1. Synaptic Vesicle Membrane Localization (GO:0030672)
  2. Most abundant integral membrane protein on synaptic vesicles
  3. Multiple lines of evidence (IBA, IEA, NAS)

  4. Represents defining localization

  5. Cholesterol Binding (GO:0015485)

  6. Direct experimental evidence (IDA)
  7. Essential for vesicle biogenesis and membrane organization

  8. PMID:10620806 demonstrates specific cholesterol binding

  9. Synaptic Vesicle Endocytosis (Modified from broad endocytosis)

  10. Critical role in regulating endocytosis kinetics
  11. Modified from GO:0006897 to GO:0048488 for specificity

  12. Essential for maintaining synaptic transmission during sustained activity

  13. Synaptic Plasticity Regulation

  14. Short-term plasticity (GO:0048172) - well-documented
  15. Long-term plasticity (GO:0048169) - supported by multiple studies

  16. Acts by regulating vesicle dynamics and release probability

  17. Hexamer Formation (GO:0042802 - identical protein binding)

  18. Forms hexameric ring structures
  19. Critical for organizing synaptobrevin-2 complexes
  20. Confirmed by structural studies

Annotations Removed

  1. Protein Binding (GO:0005515) - 3 instances
  2. Rationale: Too generic and uninformative
  3. Specific interactions (VAMP2, cholesterol, synapsin) should be annotated instead

  4. Based on generic interactome studies that don't capture meaningful biology

  5. Regulation of Synaptic Vesicle Priming (GO:0010807)

  6. Rationale: Acts downstream of priming, not in regulating priming itself
  7. Knockout studies show effects on fusion, not priming

  8. Conflates priming with fusion regulation

  9. Regulation of Opioid Receptor Signaling (GO:2000474)

  10. Rationale: No evidence in primary human synaptophysin literature
  11. Likely over-interpretation from ISS annotation
  12. Not a specific function of synaptophysin

Non-Core Annotations Retained

  1. Neuromuscular Junction (GO:0031594)
  2. Present but not primary localization

  3. Main research focuses on CNS synapses

  4. Perinuclear Region (GO:0048471)

  5. Likely transient during biosynthesis

  6. Not a functional localization

  7. Schaffer Collateral-CA1 Synapse (GO:0098685)

  8. Overly specific anatomical annotation
  9. Synaptophysin is general synaptic protein

Modified Annotations

  1. Endocytosis → Synaptic Vesicle Endocytosis
  2. Original: GO:0006897 (endocytosis)
  3. Proposed: GO:0048488 (synaptic vesicle endocytosis)
  4. Rationale: Captures the specific biological process more accurately

Evidence Sources

Key Publications

Primary Evidence Sources

Molecular Functions

Confirmed Core Molecular Functions

  1. Cholesterol binding (GO:0015485) - IDA evidence
  2. Identical protein binding (GO:0042802) - Hexamer formation
  3. SH2 domain binding (GO:0042169) - Via tyrosine phosphorylation sites

Biological Processes

Core Processes

  1. Synaptic vesicle endocytosis (modified from GO:0006897 to GO:0048488)
  2. Synaptic vesicle membrane organization (GO:0048499)
  3. Synaptic vesicle maturation (GO:0016188)
  4. Regulation of short-term neuronal synaptic plasticity (GO:0048172)
  5. Regulation of long-term neuronal synaptic plasticity (GO:0048169)
  6. Modulation of chemical synaptic transmission (GO:0050804)

Cellular Components

Primary Localizations

  1. Synaptic vesicle membrane (GO:0030672) - Core localization
  2. Presynaptic active zone (GO:0048786) - Functional site
  3. Presynapse (GO:0098793) - Exclusive presynaptic localization
  4. Terminal bouton (GO:0043195) - Nerve terminals

Recommendations

For GO Curators

  1. Replace generic "protein binding" annotations with specific molecular function terms:
  2. Consider annotations for VAMP2/synaptobrevin-2 binding
  3. Consider annotations for synapsin binding

  4. Consider annotations for V-ATPase interaction

  5. Add missing specific functions:

  6. Membrane elastomer function
  7. Regulation of vesicle size

  8. Regulation of release probability (inhibitory role)

  9. Clarify priming vs. fusion regulation:

  10. Current annotation conflates these processes
  11. Synaptophysin acts downstream of priming on fusion itself

Future Annotation Priorities

  1. Document interaction with synaptobrevin-2 (VAMP2)
  2. Document role in organizing synaptic vesicle clusters with synapsin
  3. Document membrane elasticity function
  4. Document V-ATPase interaction (recent discovery)
  5. Document role as inhibitor of neurotransmitter release

Notes