SIA1 (YOR137C, Q12212) — curation notes

Journal / working notes for the AI GO-annotation review of Saccharomyces cerevisiae SIA1.

Identity

UniProt: Q12212 (SIA1_YEAST); systematic name YOR137C; ORF YOR3329C; chromosome XV.
SGD: S000005663.
Length 622 aa; PE=2 (evidence at transcript level).
Gene name origin: SIA1 = "Suppressor of eIF5A 1" — verified against the SGD backend record
(name_description: "Suppressor of eIF5A", cited to Valentini SR et al. 2002, PMID:11861547).
NOTE: the task brief glossed the acronym as "Sphingoid long-chain base Influences ATPase"; this
is NOT the SGD-authoritative expansion, and I found no source for the sphingoid gloss. I use the
SGD name.
SGD one-line description: "Protein of unassigned function; involved in activation of the Pma1p
plasma membrane H+-ATPase by glucose; contains peptide signal for membrane localization."
SGD curated GO summary: Molecular Function = Unknown; Biological Process = proton transmembrane
transport; Cellular Component = Unknown. → genuinely a dark/understudied gene.

KNOWN (evidence-supported)

Required for glucose-triggered post-translational activation of the Pma1 plasma-membrane
H+-ATPase. PMID:9450541 The same abstract:
"the YOR137c gene product is implicated in this activation" and "We propose that at least two
independent mechanisms are involved in glucose activation of the H+-ATPase." This is the sole
experimental functional characterisation (deletion phenotype, IMP-grade). It shows SIA1 is
REQUIRED for the Vmax increase but does NOT show a direct molecular mechanism or a direct
physical interaction with Pma1.
Isolated genetically as a multicopy suppressor of a temperature-sensitive eIF5A (TIF51A)
allele — the basis of the gene name (Valentini et al. 2002, PMID:11861547). The abstract
names PAB1, PKC1, WSC1, WSC2, WSC3 among six suppressors and connects eIF5A to the WSC/PKC1
cell-wall-integrity signalling pathway; SIA1 is the sixth (unnamed in the abstract; full text
not in cache). This links SIA1 genetically to PKC1/cell-integrity signalling, but the mechanism
is unknown.
Induced (up-regulated) by ethanol / short-term ethanol stress (UniProt INDUCTION line,
ECO:0000269|PubMed:11389906; Alexandre et al. 2001). This is expression regulation, not a
molecular function.
Contains an N-terminal signal peptide (residues 1–27, ECO:0000255) and a metallophosphatase
domain (see below); consistent with membrane/secretory-pathway localisation, matching the
"peptide signal for membrane localization" phrasing in SGD. No experimentally verified
subcellular localisation term is curated (CC = Unknown at SGD).

Domain / bioinformatic reasoning (inline, from SIA1-uniprot.txt)

Pfam PF00149 Metallophos (one copy); InterPro IPR004843 (Calcineurin-like_PHP) +
IPR029052 (Metallo-depent_PP-like); Gene3D 3.60.21.10; SUPFAM SSF56300 Metallo-dependent
phosphatases. → SIA1 has a calcineurin-like metallophosphoesterase (MPE) fold.
PANTHER family PTHR32440, subfamily SF0 "PHOSPHATASE DCR2-RELATED". Reviewed SF0 members
(from PTHR32440-entries.csv): S. cerevisiae DCR2 (Q05924, "Phosphatase DCR2"), the K. lactis
SIA1 ortholog (Q6CPQ2), S. pombe SPCC1020.05, and several Arabidopsis "probable INACTIVE purple
acid phosphatase" proteins (PAP14/16/28/29). The local PTHR32440 PAINT cache has
GO:0004721 phosphoprotein phosphatase activity on PANTHER:PTN001286392, seeded from
SGD:S000004353 / DCR2, matching the 2017 IBA node in SIA1 GOA.
Metallophosphatase catalytic signature (the conserved metal-coordinating blocks
D-x-H…GD-x-x-D…GNH[D/E]…GH-x-H). Manual inspection of the SIA1 sequence finds candidate motifs:
QITDFHF (~315, DxH), VVITGDLLDS (~350, GD..D), and SCGHEHNNDCC (~575, GH-x-H). So at least
part of the metal-binding scaffold appears retained. HOWEVER: (a) no phosphatase substrate or
catalytic activity has ever been demonstrated for SIA1 experimentally; (b) its nearest orthologs
cluster with "inactive purple acid phosphatases"; (c) SGD lists Molecular Function = Unknown.
→ The molecular activity of SIA1 is UNRESOLVED. The IBA "phosphoprotein phosphatase activity" is
a plausible family-level inference but is NOT experimentally supported for SIA1, and may reflect a
degenerate / pseudophosphatase domain. I treat catalytic phosphatase activity as a knowledge gap,
not an established function. (This is a family-level bioinformatic judgement, not a definitive
claim of inactivity.)

Existing GOA annotations (5) — review plan

#	Term	Ev	Ref	Plan
1	GO:0004721 phosphoprotein phosphatase activity	IBA	GO_REF:0000033	KEEP_AS_NON_CORE — family-level MPE inference; not experimentally shown; flag as gap
2	GO:0016787 hydrolase activity	IEA	GO_REF:0000002 (InterPro IPR004843)	KEEP_AS_NON_CORE — generic parent of the MPE-fold inference; uninformative but not wrong
3	GO:1902600 proton transmembrane transport	IMP	PMID:9450541	MODIFY → regulation of proton transport (GO:0010155); SIA1 regulates, does not transport
4	GO:0003674 molecular_function (root, ND)	ND	GO_REF:0000015	ACCEPT (ND placeholder; MF genuinely unknown)
5	GO:0005575 cellular_component (root, ND)	ND	GO_REF:0000015	ACCEPT (ND placeholder; CC genuinely unknown)

Rationale for #3 MODIFY (not REMOVE): PMID:9450541 is experimental (IMP) and I must not overrule
the SGD curator. But the term chosen (proton transmembrane transport, a transporter/BP for the
ion movement itself) attributes the transport activity to SIA1, whereas the paper shows SIA1 is
REQUIRED for the glucose-triggered Vmax increase of Pma1 — i.e. a regulatory role. MODIFY to
"regulation of proton transport" (GO:0010155) keeps the experimental support while stating the
biology more accurately. Keep the original as the essence-is-sound case.

core_functions (planned)

SIA1 is best summarised as a positive regulator required for glucose-induced activation of the
Pma1 H+-ATPase; molecular mechanism unknown. I will use the BP "regulation of proton transport"
(GO:0010155) grounded in PMID:9450541, and NOT assert a catalytic MF given the gap.

knowledge_gaps (the primary deliverable — dark gene)

Molecular mechanism of Pma1 activation. Does SIA1 act directly on Pma1 (as an activator /
scaffold) or indirectly (e.g. via signalling, lipid environment)? PMID:9450541 shows a
requirement, not a mechanism, and explicitly proposes "at least two independent mechanisms."
Is SIA1 a catalytically active phosphatase or a pseudophosphatase? The MPE/calcineurin-like
fold and the IBA annotation suggest possible phosphatase activity, but no substrate/activity has
been demonstrated and the closest orthologs are "inactive purple acid phosphatases." If active,
its physiological substrate (Pma1? a Pma1 kinase/phosphatase relay?) is unknown.
Direct physical partners. BioGRID lists interactions but no validated Pma1 physical
interaction is curated in UniProt (IntAct=1). Direct binding partners are unknown.
Subcellular localisation. Signal peptide predicts secretory-pathway/membrane entry, but no
experimental localisation term is curated (SGD CC = Unknown). Where SIA1 acts relative to Pma1
(plasma membrane vs. secretory compartments) is unresolved.
Relationship to eIF5A / PKC1 cell-integrity signalling. SIA1 was isolated as an eIF5A
suppressor (PMID:11861547) linking it to WSC/PKC1 signalling; whether this is mechanistically
related to its Pma1 role, or an independent activity, is unknown.
Broader phenotype. SGD large-scale phenotypes (altered chemical/UV resistance, abnormal
vacuolar morphology, competitive-fitness changes) are unexplained at the molecular level.

2026-09-29 IBA re-review

Re-read the cached primary papers for the SIA1 phenotype/name/expression trail:
PMID_9450541.md and PMID_11861547.md are abstract-only; PMID_11389906.md
is an abstract-only refetch for the UniProt ethanol-induction line.
Resolved the IBA row against SIA1-goa.tsv and interpro/panther/PTHR32440/PTHR32440-paint.tsv.
The row points to PANTHER:PTN001286392|SGD:S000004353, and the local PAINT file confirms
PTN001286392 carries GO:0004721 from the yeast DCR2 seed; QuickGO also currently
reports SGD experimental phosphoprotein-phosphatase annotations on DCR2 itself. I kept the
annotation KEEP_AS_NON_CORE, but aligned propagation_review.source_entities with the
ancestral PTN source expected by the IBA project.
Searched current literature for SIA1/YOR137C/Pma1 and found no newer paper that directly
demonstrates SIA1's molecular activity, localization, or SIA1-Pma1 contact. The 2024 Guarini
et al. Pma1 phosphoregulation paper is relevant pathway context: it places Pma1 S911-T912
phosphorylation under largely redundant Ptk1/Ptk2 kinases and Glc7 PP1 dephosphorylation
PMID:38227612. It still does not close the SIA1
mechanistic gap.

Files / provenance

UniProt: genes/yeast/SIA1/SIA1-uniprot.txt
GOA: genes/yeast/SIA1/SIA1-goa.tsv
PANTHER: interpro/panther/PTHR32440/ (metadata, PAINT, entries)
Cached pubs: publications/PMID_9450541.md (abstract only), publications/PMID_11861547.md
(abstract only), publications/PMID_11389906.md (abstract only), publications/PMID_38227612.md
(full text; Pma1 context).
Deep research: genes/yeast/SIA1/SIA1-deep-research-falcon.md, used for context only.

ND literature-search citations (2026-11-06)

existing_annotations[4], GO:0005575 cellular_component (ND, GO_REF:0000015), ACCEPT: the ND may be stale. SIA1-deep-research-falcon.md states that in the Huh et al. (2003) genome-wide GFP localization study (PMID:14562095) Sia1p localizes to the cytoplasm. If that is right, a localization screen identifies a location for this gene product in S. cerevisiae. GOA carries no HDA cytoplasm row for SIA1, so the falcon claim needs checking against the Huh et al. dataset before any CC annotation is made. The review action was left unchanged.