ER–Plasma Membrane Tethering — Obsoletion & Replacement (GO:0061817)

SCOPING OBSOLETIONFLAGSHIP

Species: human, yeast, ARATH

Genes: VAPA

ER–Plasma Membrane Tethering — Obsoletion & Replacement (GO:0061817)

Bottom line: GO has obsoleted the process term GO:0061817
endoplasmic reticulum-plasma membrane tethering, because holding the ER
against the plasma membrane is a molecular function. Annotations move to the
function term GO:0160214 endoplasmic reticulum-plasma membrane adaptor
activity, with GO:0051643 endoplasmic reticulum localization for any
process aspect. We recorded the upstream plan, the affected groups (CGD 4,
PomBase 13, TAIR 2, UniProt 2) and the eight InterPro2GO mappings InterPro has
already removed, and checked the repo (grep -rl over all files under
genes/). No review YAML or GOA file uses either term, and no dedicated ER-PM
tether (extended synaptotagmins, tricalbins, plant SYTs) has been reviewed.
Human VAPA, a broad ER contact-site adaptor, never carried GO:0061817 as a
GO annotation here: the term is absent from its GOA file (in every committed
version) and its review. It appears only as a cross-reference line
(IDA:UniProtKB) in the cached UniProt flat file. VAPA has now been assessed for
GO:0160214 and not annotated (PR #3220). The term's definition requires the adaptor
itself to bind plasma-membrane lipids, and at VAPA contacts that is done by the
partner's PH domain (e.g. ORP3). Scoped, not yet started for the tethers
proper: the obsoletion has since landed (OLS lists GO:0061817 as obsolete),
which makes this family a timely candidate for new reviews, starting with human
ESYT2 and yeast TCB3.

Overview

A GO obsoletion proposal will retire GO:0061817 endoplasmic reticulum–plasma
membrane tethering (a BP term). The rationale is that the activity is better
captured at the molecular function level by GO:0160214 endoplasmic
reticulum–plasma membrane adaptor activity, with the broader spatial
consequence captured by GO:0051643 endoplasmic reticulum localization (BP).

This project tracks the impact on AI Gene Review and queues affected gene
families for review, given that none of the canonical ER–PM tether proteins
(extended synaptotagmins, tricalbins, plant synaptotagmins) have been reviewed
yet in this repository.

Upstream tickets

Obsoletion plan (per upstream)

Obsoleted term ID Replacement candidates
endoplasmic reticulum–plasma membrane tethering GO:0061817 MF: GO:0160214 endoplasmic reticulum–plasma membrane adaptor activity; BP: GO:0051643 endoplasmic reticulum localization

Affected upstream groups (from issue body)

Group Annotations Status
CGD (Candida Genome Database; Candida species not recorded upstream) 4 pending
PomBase 13 DONE
TAIR (Arabidopsis) 2 pending
UniProt 2 per latest comment, "uniprot updated"

InterPro2GO mappings (per latest upstream comment, term removed by InterPro)

These eight InterPro entries previously mapped to GO:0061817 and have since had
the mapping removed (will appear in InterPro release 109.0):

InterPro ID Family Maps to (organisms)
IPR017147 Tricalbin yeast Tcb1/2/3
IPR037761 Tricalbin C2A domain yeast Tcb1/2/3
IPR037765 Tricalbin C2B domain yeast Tcb1/2/3
IPR037762 Tricalbin C2C domain yeast Tcb1/2/3
IPR037756 Tricalbin C2D domain yeast Tcb1/2/3
IPR037733 Extended synaptotagmin C2A domain mammalian ESYT1/2/3 and plant SYT1/SYT5
IPR037749 Extended synaptotagmin C2B domain mammalian ESYT1/2/3
IPR037752 Extended synaptotagmin C-terminal C2 domain mammalian ESYT1/2/3

Impact on this repo

No genes in the ER–PM tether family are currently reviewed. A search for ESYT,
TCB, tricalbin, or synaptotagmin under genes/ returned no matches, and no
*-ai-review.yaml or *-goa.tsv file contains GO:0061817 or GO:0160214.

A search across all file types (grep -rl GO:0061817 genes/) finds one
hit: genes/human/VAPA/VAPA-uniprot.txt:505, a DR line in the cached UniProt
flat file (entry version 220, 2026-09-02)
GO:0061817 endoplasmic reticulum-plasma membrane tethering; IDA:UniProtKB.
That line is UniProt's own cross-reference, not a GOA row. VAPA-goa.tsv has
no GO:0061817 row in any committed version, and the review has never used the
term, so no VAPA annotation needs repair for the obsoletion. The two
statements that VAPA "carries GO:0061817 in its cached UniProt record" and
"carries no GO:0061817 annotation in GOA" (the VAPA notes in PR #3220) are
both true; they describe different files.

VAPA is an ER-resident FFAT-motif adaptor whose review describes it as
organizing contact sites with endosomes, Golgi and plasma membrane, with core
molecular function GO:0043495 protein-membrane adaptor activity. It was the
one repo gene where "does GO:0160214 apply?" was already live, and PR #3220
answers it: not annotated. GO:0160214 is defined as bringing the plasma
membrane and ER membrane together "via membrane lipid binding". At
VAPA-dependent ER-PM contacts the plasma-membrane lipid binding is done by the
FFAT partner (e.g. the ORP3 PH domain binding PI(4,5)P2), while VAPA is the
ER-anchored FFAT receptor, already captured by GO:0043495. PomBase does annotate
the fission-yeast VAP orthologs scs2 and scs22 to GO:0160214, and UniProt
transfers it to human VAPB (ISS), so the review records this as a
suggested_questions entry rather than settling it. No other review needs refresh for the obsoletion itself; the
tether family proper is well-characterized in the literature and represents a
coherent candidate set for proactive review.

Scope

Candidate genes for initial review

Verify each with just fetch-gene <organism> <gene> before starting; do not
add files without confirming the UniProt accession from the UniProt API.

Mammalian Extended Synaptotagmins (E-Syts)

  1. ESYT1 (human) — extended synaptotagmin-1; major Ca²⁺-regulated ER–PM
    tether; recruited to junctions at elevated cytosolic Ca²⁺ (Ca²⁺-dependent
    MCS expansion).
  2. ESYT2 (human) — extended synaptotagmin-2; constitutive ER–PM tether
    active at resting Ca²⁺.
  3. ESYT3 (human) — extended synaptotagmin-3; constitutive ER–PM tether,
    functionally redundant with ESYT2.

S. cerevisiae Tricalbins

  1. TCB1 (SGD: YOR086C) — yeast tricalbin-1; cortical ER–PM tether.
  2. TCB2 (SGD: YNL087W) — yeast tricalbin-2; cortical ER–PM tether.
  3. TCB3 (SGD: YML072C) — yeast tricalbin-3; cortical ER–PM tether; the
    triple Δtcb1/2/3 mutant is the canonical loss-of-MCS phenotype.

Plant Synaptotagmins (TAIR)

  1. SYT1 (Arabidopsis, AT2G20990) — most-studied plant ER–PM tether;
    Ca²⁺-regulated; involved in stress-induced membrane contact stabilization.
    Likely candidate for one of the two TAIR annotations under review upstream.
  2. SYT5 (Arabidopsis) — additional plant ER–PM tether; redundant with SYT1.

Lower priority / verification only

  1. CGD-affected Candida orthologs (species to confirm from the CGD rows) — 4 annotations upstream; not a
    primary AI Gene Review focus organism. Defer unless the broader project
    expands to fungal pathogens.

Proposed approach

  1. Wait for the obsoletion decision. Comment thread on
    geneontology/go-ontology#31873 should be monitored; the InterPro mappings
    have already been removed (per comment from Sara), so the upstream work
    is partly underway.
  2. Once the obsoletion lands, the replacement MF term GO:0160214 will be
    the natural ACCEPT for core-function annotations of these tethers. Reviews
    should propose this MF and either GO:0051643 (ER localization) or a more
    informative BP child term (membrane contact site organization etc.) for
    process-level annotation.
  3. VAPA: done (PR #3220). Assessed for GO:0160214 and not annotated,
    because the PM lipid binding at VAPA contacts is the partner's. Whether
    the term should cover ER-anchored FFAT receptors (the PomBase scs2/scs22
    and UniProt VAPB precedent) is raised as a suggested question.
  4. Begin with ESYT2 + TCB3 as anchor reviews — these are the most
    structurally and biochemically characterized members and have the cleanest
    literature support for the adaptor/tether MF call.
  5. Use the family as a coherent batch — once one member is reviewed, the
    others can leverage shared references and core-function language.
  6. For TAIR plant SYTs, defer until ESYT/TCB reviews establish the
    template; plant annotations also require careful handling of stress/drought
    phenotypes vs. core MCS function.

Priority

Medium. The biology is well-established and reviews would be high-quality,
but no existing reviews are blocked by the obsoletion. This is opportunistic —
the family is unreviewed in the repo, the obsoletion makes it timely, and the
membrane contact site (MCS) area has been growing in interest.

Status

Slides