Mitochondrion–ER Membrane Tethering — Obsoletion & Replacement (GO:1990456)

Overview

A GO obsoletion proposal will retire GO:1990456 mitochondrion-endoplasmic
reticulum membrane tethering (a BP term). The rationale matches the parallel
ER–PM and peroxisome–chloroplast tether obsoletions: the activity is more
appropriately captured at the molecular function level by the existing
GO:0140474 mitochondrion-endoplasmic reticulum membrane tether activity.

This project tracks the impact on AI Gene Review and queues the canonical
mitochondrion–ER tether proteins for review.

Upstream tickets

• Annotation tracker: geneontology/go-annotation#6397
• Ontology ticket: geneontology/go-ontology#31875

Obsoletion plan (per upstream)

Obsoleted term	ID	Replacement
mitochondrion-endoplasmic reticulum membrane tethering	GO:1990456	MF: GO:0140474 mitochondrion-endoplasmic reticulum membrane tether activity

Affected upstream groups (from issue body)

Group	Annotations	Status
CACAO	1	pending
ComplexPortal	9	pending
FlyBase	1	DONE
MGI	1	pending
SGD	6	DONE
UniProt	7	DONE
dictyBase	5	pending

Mappings to be reviewed

Source	Mapping
InterPro2GO	InterPro:IPR039275 (PDZ domain-containing protein 8) → GO:1990456
HAMAP2GO	HAMAP:MF_03102 (MDM10 family — ERMES component) → GO:1990456
UniRule2GO	UniRule:UR000106107 → GO:1990456

Impact on this repo

The obsoletion intersects existing reviews in the following way:

Gene	Organism	Existing action on GO:1990456
VMP1	human	annotated with GO:1990456 in genes/human/[VMP1](../../genes/human/VMP1/VMP1-ai-review.html)/VMP1-ai-review.yaml
CALM1	human	GO:1990456 row currently ACCEPT
Calm1	mouse	GO:1990456 row present
Calm2	mouse	GO:1990456 row present
Calm3	mouse	GO:1990456 row present

These reviews will need a refresh once the obsoletion lands — for VMP1 and the
calmodulin family the GO:1990456 annotation should be reassessed against
GO:0140474 (or, for calmodulins, likely REMOVED because the evidence does
not show that calmodulin itself is a mitochondrion–ER tether). Human VMP1 and
CALM1 carry UniProt IDA annotations from PMID:28890335. Mouse Calm1/2/3 carry
computational or similarity-propagated annotations (IEA/ISO/ISS), not Reactome
TAS annotations.

Human CALM2 is not currently present in this repository, and human CALM3 does
not currently have a GO:1990456 row in either GOA or the review YAML.

No canonical mito–ER tether genes (ERMES components, PDZD8, MFN2,
VAPB/PTPIP51) are currently reviewed in this repository.

Scope

• Organisms: human (PDZD8, MFN2, VAPB, PTPIP51), S. cerevisiae (ERMES
  components: MMM1, MDM10, MDM12, MDM34), Dictyostelium (5 dictyBase
  annotations still pending), mouse (1 MGI annotation pending).
• GO branches: BP (the obsoleted term itself) and MF GO:0140474. Both
  belong to the membrane contact site (MCS) branch.
• Type of fix: terminological in GO; biology is well established. Reviews
  should evaluate whether the MF replacement (tether activity) is the better
  core-function term and add it where the underlying assay supports it.

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 mito–ER tethers

1. PDZD8 (human) — PDZ domain-containing protein 8. Direct target of the
   InterPro2GO mapping (IPR039275). Vertebrate functional analog of yeast
   Mmm1; established mito–ER tether (Hirabayashi et al. 2017, Science).
2. MFN2 (human) — Mitofusin-2. Long-debated mito–ER tether at MAMs
   (de Brito & Scorrano 2008, Nature), with substantial counter-evidence that
   MFN2 can instead act as a negative regulator of ER–mitochondria proximity
   (Filadi et al. 2015, PNAS).
3. VAPB (human) — VAMP-associated protein B/C. Forms a tether with
   PTPIP51 at MAMs (Stoica et al. 2014, Nat Commun).
4. PTPIP51 / RMDN3 (human) — partner of VAPB at MAMs.

Yeast ERMES complex (S. cerevisiae)

1. MMM1 — ER-anchored ERMES SMP-domain subunit. MMM1 is a sister ERMES
   subunit and should not be treated as the direct HAMAP MF_03102 target.
2. MDM10 — outer mitochondrial membrane β-barrel; ERMES + TOM-assembly
   bridge. Direct target of HAMAP MF_03102.
3. MDM12 — cytosolic SMP-domain subunit bridging Mmm1 and Mdm34.
4. MDM34 — outer mitochondrial membrane SMP-domain subunit.

Yeast SGD has already migrated its annotations upstream; review here would
serve to capture the canonical tether MF for these reference proteins rather
than to fix outstanding GOA rows.

Other organisms

1. The 5 dictyBase pending annotations are likely to be the Dictyostelium
   ERMES homologs — review opportunistically once the gene set is confirmed.

Proposed approach and priority

1. Refresh existing affected reviews (human VMP1 and CALM1; mouse
   Calm1/2/3) to revisit GO:1990456 rows once the obsoletion lands. The
   calmodulin rows likely should be REMOVED rather than rerouted, but the
   rationale should distinguish the human UniProt IDA annotation from the mouse
   computational/similarity-propagated annotations.
2. Anchor new reviews on PDZD8 + MFN2 as the highest-impact
   mammalian tethers, and on MMM1 + MDM12 for the yeast ERMES anchor
   pair.
3. Once GO:0140474 is the canonical MF term, audit other genes in this
   repository whose core_functions could legitimately gain it (e.g. through
   the proposed_replacement_terms mechanism).

Status

• Upstream FlyBase, SGD, and UniProt updates are done; CACAO (1),
  ComplexPortal (9), MGI (1), and dictyBase (5) experimental annotations are
  still pending.
• Mappings (InterPro2GO IPR039275, HAMAP MF_03102, UniRule UR000106107) all
  need to be re-pointed to GO:0140474.
• No reviews in this repo are blocked by the obsoletion; the impact is a
  refresh queue (human VMP1/CALM1 plus mouse Calm1/2/3) and a forward-looking
  review queue (PDZD8, MFN2, VAPB, PTPIP51, ERMES components).
• Recommend starting with PDZD8 as the anchor review, since it is both
  the InterPro2GO mapping target and the most recently mechanistically
  characterized mammalian mito–ER tether.