Flagged as a contested/newly-assigned molecular function case: is TMEM63B a mechanically
activated cation channel, a mechanically activated lipid scramblase, or genuinely both?
Unusually for this batch, GOA already carries both activities for TMEM63B with
experimental evidence (GO:0140135 mechanosensitive monoatomic cation channel activity IDA;
GO:0017128 phospholipid scramblase activity IDA + IMP x2 + IEA), so the curation question is
not "which one is right" but whether both are core, and how TMEM63B differs from its
paralog TMEM63A.
Both activities are core for TMEM63B. TMEM16 family proteins are the precedent for one
protein being both a channel and a scramblase, and TMEM63B belongs to the same
Transmembrane-Channel-Scramblase (TCS) superfamily fold. The channel and scramblase claims
rest on different assays and different constructs, and both sets are independently
replicated, so this is a genuine dual-function protein rather than a dispute in which one
side must be wrong.
Founding family-level demonstration that OSCA/TMEM63 proteins are mechanically activated
channels: PMID:30382938.
Structure + electrophysiology, establishing the monomeric architecture and the biophysics:
PMID:37543036 and
PMID:37543036.
In vivo physiological demonstration in mouse lung, with cation currents recorded during
stretch: PMID:38127458 and PMID:38127458.
Human disease variants act on the conductance: PMID:37421948.
Four independent groups, four different assay systems:
Mechanistic follow-up mapping an autoinhibitory C-terminal tail:
PMID:42248451, from a group that now
simply calls the protein a scramblase PMID:42248451.
They do not collapse into one another, and the 2025-2026 work shows they can be separated:
So the two activities share a groove but are not the same measurement re-described.
Whether wild-type TMEM63B scrambling operates in vivo at physiological force, as opposed to in
reconstituted/over-expressed systems, is explicitly flagged as unresolved by the authors of the
structural work: PMID:40480214. This uncertainty
is about the physiological deployment, not about whether the activity exists, so it does not
warrant demoting GO:0017128 from core — but it is recorded in suggested_questions.
GO:0005227 calcium-activated cation channel activity — wrong gating stimulusGO definition: "Enables the transmembrane transfer of an inorganic cation by a channel that
opens when a calcium cation has been bound by the channel complex or one of its constituent
parts." Every experimental user of this term in GOA is a genuinely Ca2+-gated channel
(KCNN4, SLO1/SLO2, TRPM4, TMEM16A/subdued). TMEM63B is gated by membrane stretch and
hypo-osmolarity and is Ca2+-permeable, not Ca2+-gated. The provenance of the error is
visible in two places:
Action: MODIFY on all four GO:0005227 rows (IBA, IEA, IDA, ISS) → GO:0140135
mechanosensitive monoatomic cation channel activity + GO:0005262 calcium channel activity.
GO:0120019 phosphatidylcholine transfer activity / GO:0140338 sphingomyelin transfer activity — wrong mechanismGO:0120019: "Removes phosphatidylcholine from a membrane or a monolayer lipid particle,
transports it through the aqueous phase while protected in a hydrophobic pocket, and brings
it to an acceptor membrane". GO:0140338 is the same shape for sphingomyelin. These describe
soluble intermembrane lipid-transfer proteins (STARD/CERT-like), not polytopic membrane
scramblases. TMEM63B is an 11-TM integral membrane protein that flips PC and SM between the two
leaflets of one bilayer. The observation behind the annotation is real
(PMID:39424995) but it was mapped to a transfer-protein term rather than a scramblase term.
Action: MODIFY both → GO:0017128 phospholipid scramblase activity (which the gene already
carries with IDA/IMP). Note that GO has no lipid-species-specific scramblase child; a
phosphatidylcholine scramblase activity / sphingomyelin scramblase activity term is
proposed in proposed_new_terms.
The downstream GOC-derived GO:0015914 phospholipid transport (derived from GO:0120019) is
correct but uninformative; MODIFY to GO:0017121 plasma membrane phospholipid scrambling,
which the gene already carries and which is a descendant of GO:0015914.
TMEM63B and TMEM63A are not interchangeable for the scramblase claim. The Segawa-lab
paralog survey found scrambling for vertebrate TMEM63B orthologs but not for the human
paralogs, and GOA records this as NOT|enables GO:0017128 on TMEM63A (IDA, PMID:39716028).
The 2026 GUV work agrees for the cellular setting:
PMID:41617699. So the
paralog difference is real at the level of cellular scrambling; TMEM63A can scramble only
when purified and reconstituted, or when cells are actively stretched.