Deep research was unavailable in this container (Falcon returned HTTP 402, OpenAI
HTTP 401, perplexity not registered). No -deep-research-*.md file was generated. The
synthesis below was assembled manually from the cached publications in publications/,
the UniProt record SLC10A4-uniprot.txt, and the GOA file SLC10A4-goa.tsv.
SLC10A4 (also called VAAT, "vesicular aminergic-associated transporter") is the fourth
member of the SLC10 / bile acid:sodium symporter (BASS, TC 2.A.28) family, whose founding
members are the hepatic bile salt carrier NTCP (SLC10A1) and the ileal carrier ASBT
(SLC10A2). It is a 437-residue, seven-transmembrane integral membrane protein with an
N(exo)/C(cyt) orientation and an unusually long extracellular N-terminus relative to
SLC10A1/A2/A6 PMID:18355966.
It is an orphan carrier: no substrate has been identified. This is the single most
important fact for the annotation review, and it is supported by four independent
laboratories using four different expression systems:
The field's own framing is unambiguous PMID:28439090.
Unlike NTCP/ASBT, SLC10A4 is not a bulk plasma-membrane carrier at steady state. It is a
synaptic-vesicle protein of cholinergic and monoaminergic neurons, and a granule protein of
mast cells:
A plasma-membrane pool is nonetheless reported in heterologous overexpression, alongside
intracellular compartments PMID:17106928, and UniProt records SUBCELLULAR LOCATION: Cell membrane
with ECO:0000269|PubMed:23589386. So located_in plasma membrane is defensible as a
secondary/overexpression location; is_active_in plasma membrane is not where any
functional effect of this protein has ever been measured.
Every reproducible functional effect is a modulation of a vesicle's or granule's
properties, measured by loss or gain of SLC10A4 rather than by any activity assayed on the
protein itself:
These are knockout/overexpression phenotypes — necessity and dose-sensitivity evidence.
Per the participation test in CLAUDE.md, they do not by themselves identify which entity
performs the step (VMAT2 performs monoamine loading; the V-ATPase performs acidification),
so no NEW process annotation is proposed from them. They are recorded instead in
suggested_questions and suggested_experiments.
SLC10A4 heterodimerizes with NTCP and reduces NTCP surface abundance and taurocholate
uptake PMID:22029531,
PMID:22029531, reproduced by an independent group
PMID:31256060, PMID:31256060.
Note the sign: this is a negative effect on bile salt uptake by a partner protein, and it
has only been shown in forced co-expression (U2OS, HEK293, yeast split-ubiquitin). Native
expression is also largely non-overlapping — SLC10A4 is brain/intestine-enriched while NTCP
is hepatocyte-specific. So this evidence does not support involved_in bile acid and
bile salt transport, and is far too indirect to support a regulation-of-transport term
either. It is raised as a question for experts rather than asserted.
The GOA row is NOT|enables GO:0008508 bile acid:sodium symporter activity, IMP,
ECO:0000315, from PMID:23589386, assigned by UniProt. It is a negated annotation —
it asserts the absence of the activity.
PMID:23589386 is abstract-only in the cache (full_text_available: false). Its title
("SLC10A4 is a protease-activated transporter that transports bile acids") reads as a
positive claim, but the abstract both opens with the negative baseline and qualifies the
positive conclusion heavily:
What the paper actually demonstrates is that thrombin treatment of TE671 cells increases
LCA/TCA accumulation, and that siRNA against SLC10A4 abolishes that increment. That is an
SLC10A4-dependent, protease-dependent uptake phenotype in whole cells. It is not a
demonstration of symport: no sodium dependence, stoichiometry, saturation kinetics, or
activity in a reconstituted or heterologous system is reported, and the measured
baseline activity is explicitly "no transport activity for bile acids".
The UniProt curator, who read the full text, drew the same conclusion and recorded it
twice: the negated GO row, and the FUNCTION comment "No significant bile acid transporter
activity could be measured despite its similarity to bile acid:sodium symporters."
(ECO:0000269|PubMed:23589386). This agrees with the four independent negative studies
above.
Verdict: ACCEPT the negated annotation. The NOT is the correct reading of this paper
and of the field. No action is taken against the curator; the MODIFY/
MARK_AS_OVER_ANNOTATED options that would apply to a positive IMP of symport activity
are not in play, because GOA does not assert the positive. (This is worth flagging: the
annotation was initially briefed to this review as a positive IMP. The negated: true
flag in the review YAML and the NOT|enables qualifier in the GOA tsv settle it.)
The inconsistency that does need fixing is elsewhere in the same GOA record: a
GO:0015721 bile acid and bile salt transport IBA sits alongside the NOT, propagated from
the rat bile acid carriers via PANTHER:PTN000040761. The experimental negation and the
phylogenetic inference contradict each other, and the experimental evidence (five
independent studies) wins. That row is REMOVE.
GO:0022857 transmembrane transporter activity (IBA, PTN000040756) and its logically
inferred GO:0055085 transmembrane transport (IEA, GO_REF:0000108) are both deliberately
shallow. For a protein that demonstrably retains the BASS fold and seven-TM topology but
whose substrate has defeated four laboratories, this is exactly the right level of
specificity: it commits to carrier-type architecture without committing to a cargo. Both
are ACCEPT, and the reviews say explicitly that they should not be deepened until a
substrate is identified. An argument could be made that even the parent overstates matters
(SLC10A4 may act as a vesicular regulator rather than a carrier), but the PAINT node
placement is a judgement about where the carrier activity arose in the family, and there is
no target-specific evidence of fold loss to argue against it.
Five GO:0005515 protein binding IPI rows from HuRI PMID:32296183 name TMEM218
(A2RU14), COL4A5 isoform 2 (P29400-2), VMA12/TMEM199 (Q8N511), SLC35A4 (Q96G79) and
DNAJC30 (Q96LL9) — all also listed in the UniProt INTERACTION block with NbExp=3. The
partners are membrane/ER proteins, which is broadly consistent with SLC10A4's membrane
residency, but none supports a specific informative molecular function. Per the Quality
Standards section of SKILL.md these are REMOVE as uninformative; removal does not imply
the interactions are false.
A core molecular function cannot be assigned with a substrate. The single core-function
entry uses GO:0022857 transmembrane transporter activity — the term the accepted IBA
already supports — with the location moved to GO:0030672 synaptic vesicle membrane, and
the description states plainly that the transported substrate is unidentified. No
proposed_new_terms entry is created: inventing a term such as "vesicular neurotransmitter
loading accessory activity" would assert a mechanism that the knockout-level evidence does
not establish.
| Action | Count | Rows |
|---|---|---|
| ACCEPT | 4 | GO:0008508 (NOT, IMP), GO:0016020 (IEA), GO:0022857 (IBA), GO:0055085 (IEA) |
| KEEP_AS_NON_CORE | 2 | GO:0005886 located_in (IDA), GO:0005886 located_in (IEA) |
| MODIFY | 1 | GO:0005886 is_active_in (IBA) → GO:0030672 synaptic vesicle membrane |
| REMOVE | 6 | 5 × GO:0005515 (IPI, HuRI), GO:0015721 (IBA) |