VCL (vinculin, human, UniProt P18206) -- review notes

Automated deep research was unavailable for this gene (no deep-research provider
keys in this environment). These notes were written manually from the UniProt
entry (VINC_HUMAN), the cached publications cited by GOA (see
full_text_available: in each publications/PMID_*.md), and three cached
papers on premetazoan vinculin (PMID:29880641, PMID:32857975, PMID:20479219).

Identity and structure

• 1134-aa metavinculin (isoform 2, displayed) / 1066-aa vinculin (isoform 1);
  member of the vinculin/alpha-catenin family (PANTHER PTHR46180; InterPro
  IPR006077, IPR017997). Single gene on 10q
  PMID:2116004.
  Metavinculin (68-residue tail insert) is muscle-specific (UniProt).
• Head (Vh, D1-D4) + proline-rich hinge + tail (Vt). Head-tail interaction
  autoinhibits; the tail carries the F-actin binding site
  PMID:7816144;
  PMID:7816144.

Molecular activities

• Actin filament binding (tail; cryptic in the closed molecule)
  PMID:7816144.
  GOA has only generic actin binding (IDA, PMID:16803572, abstract-only) and a
  NOT actin binding (IDA, PMID:7816144). The NOT row reflects the
  autoinhibited full-length protein in vitro; the same paper establishes a
  cryptic F-actin site, so the NOT row misrepresents the gene product. Proposed
  NEW actin filament binding (GO:0051015).
• Talin binding (D1 head; activates vinculin)
  PMID:15070891;
  review PMID:10320934.
• alpha-actinin binding (D1)
  PMID:15988023.
• alpha-catenin binding
  PMID:9700171.
• beta-catenin binding (requires vinculin A50; binds beta-catenin N-terminus)
  PMID:20086044.
• Arp2/3 complex binding (hinge)
  PMID:12473693.
• SH3 domain binding (proline-rich hinge binds SoHo-family adaptors)
  PMID:9885244;
  CAP/SORBS1 PMID:17082770.
• Pathogen mimicry of talin: Shigella IpaA and Rickettsia Sca4 bind and activate
  vinculin PMID:17932491;
  PMID:21841197.
  Real, but host-pathogen; generic protein binding rows removed.
• No GO term exists for paxillin binding (QuickGO search 2026-10-01), so the
  paxillin IPI row (PMID:9054445) cannot be converted.
• Cadherin binding: vinculin reaches cadherins through alpha- and beta-catenin,
  not by binding the cadherin tail itself
  PMID:20086044.
  cadherin binding (HDA from the E-cadherin proximity interactome, ISS) is an
  over-annotation.

Processes and locations

• Cell-matrix adhesions: focal adhesions, costameres, podosomes; strengthens
  integrin-talin-actin linkage
  PMID:21423176.
  Not required to assemble focal adhesions
  PMID:10320934; regulates
  adhesion dynamics and migration
  PMID:15494027.
• Cell-cell junctions: required for E-cadherin surface stability in MCF10A cells
  via beta-catenin PMID:20086044;
  alpha-catenin-vinculin interaction organizes the apical junctional complex
  PMID:9700171.
  Note PMID:9700171 genetics was in mouse F9 vinculin-null cells; binding data used
  chick gizzard lysate.
• Endothelium: force-dependent partitioning between FA (talin) and AJ
  (VE-cadherin) PMID:26923917;
  PMID:25753039.
• Lamellipodial protrusion via Arp2/3 recruitment
  PMID:12473693.
• Platelet aggregation HMP (PMID:23382103) is correlative (lower vinculin in MDS
  platelets among many proteins) -> over-annotation.
• Maintenance of blood-brain barrier NAS (PMID:30280653): the cached full text of
  this review does not mention vinculin at all -> over-annotation.
• Reactome granule-lumen / extracellular-region TAS rows derive from
  degranulation/platelet-release proteomics; vinculin is a cytoplasmic protein
  without a signal peptide -> over-annotation.

GO-CAM

gocams/index.tsv has no row for VCL (human P18206) or mouse/rat Vcl
(checked 2026-10-01). No GO-CAM role to reconcile.

IBA rows

All IBA rows come from PANTHER node PTN005285701 (vinculin/alpha-catenin
family node with Dictyostelium donors). Locations (cytoplasm, cytoskeleton,
plasma membrane, focal adhesion, adherens junction, cell-cell contact zone) and
cell adhesion are well grounded, and P18206 itself appears among the donors for
several -- expected, not circular. The beta-catenin binding IBA has P12003
(chicken vinculin) and a Dictyostelium member as donors; Dictyostelium
alpha-catenin-like proteins bind the beta-catenin homolog Aardvark, so the node
may be capturing an alpha-catenin-type activity. Human vinculin has its own
experimental support (Peng 2010), so the IBA is accepted for VCL, but the node
placement is worth checking because sponge vinculin did not bind a
beta-catenin peptide (below).

Premetazoan / evolutionary context

• Vinculin/alpha-catenin family proteins predate animals
  PMID:29880641.
• Integrin adhesome scaffolds are ancient
  PMID:20479219.
• Capsaspora (unicellular filasterean): vinculin localizes with integrin beta2 in
  adhesive filopodia (abstract-only; antibody specificity not inspectable)
  PMID:32857975.
• Sponge Oscarella pearsei vinculin (repo review genes/OSCPE/VIN1/): binds talin,
  talin peptide releases F-actin binding
  PMID:29880641;
  did not bind a beta-catenin peptide
  PMID:29880641;
  localizes to cell-cell contacts and filopodia in tissue.
• Caveat on the beta-catenin negative: the sponge beta-catenin peptide
  corresponded to the alpha-catenin-binding region of beta-catenin, whereas human
  vinculin binds the beta-catenin N-terminus (PMID:20086044, M8P mutant). So the
  sponge result does not directly test the vinculin-beta-catenin interface
  characterised in mammals.

Synthesis (ancestral vs animal-specific):
- Ancestral (premetazoan): talin-activated, autoinhibited actin filament binding
and the talin/integrin cell-substrate linkage (sponge biochemistry; Capsaspora
filopodial co-localization with integrin; adhesome gene content).
- Animal-specific (plausible, not demonstrated): coupling to cadherin-catenin
junctions via alpha-catenin and beta-catenin, apical junction assembly, and
tissue-level roles (endothelial barrier, intercalated disc, costamere with
metavinculin). Sponge vinculin sits at cell-cell contacts, so recruitment to
cell-cell junctions dates at least to the sponge-bilaterian ancestor; the
beta-catenin interface is untested outside bilaterians in a matched assay.

Decisions summary

See VCL-ai-review.yaml. Key: protein binding rows converted to talin binding,
alpha-actinin binding, Arp2/3 complex binding, SH3 domain binding where the
paper supports it; others removed. NOT actin binding removed; NEW actin filament
binding. Cadherin binding marked over-annotated (indirect via catenins).