FXYD2

Summary: The activator-specific transfer is unresolved.

Reason: The literal pig Q58K79 donor carries IDA GO:0001671 from PMID:18075585 with the renal/pump context. That paper was accessed as an abstract and structural preview; its specific activation experiment was not recovered. Accessible human PMID:33231612 and mouse PMID:15755730 establish pump regulation, including lower apparent sodium affinity with FXYD2 under the tested conditions. An ion-affinity endpoint is not a universal measure of stimulation of ATP hydrolysis or turnover: in the human comparison, FXYD1 shares the baseline affinity direction, while other experiments establish its phosphorylation-dependent positive regulation. The sign-neutral parent is supported, but those observations neither verify the specific pig-derived activation claim nor exclude activation in another defined condition. Retain UNDECIDED for that source-specific transfer, preserving the original ISS, five extension atoms and alpha1 input.

Summary: The plasma membrane is the site of pump-complex function.

Reason: The retained Reactome R-HSA-936897 summary explicitly describes the alpha/beta/FXYD pump exchanging sodium and potassium across the plasma membrane. Human FXYD2b surface pump currents provide independent functional support. This location is retained without assigning the reaction catalysis or every cardiac pathway context in the summary to FXYD2.

Summary: Retain plasma-membrane localization in the glycoside-bound pump context.

Reason: The retained R-HSA-9684068 entry describes glycoside binding to the ATP1A:ATP1B:FXYD pump. The annotation is a plasma-membrane location, which is independently consistent with human FXYD2b functional pump expression. It does not assert that FXYD2 is the glycoside receptor or independently mediates Tat secretion; the summary chiefly attributes those endpoints to the catalytic pump component.

Summary: Retain the rat-derived pump-complex membership inference.

Reason: Rat Q04679 has IDA complex evidence from PMID:12626497, whose gamma association and transport experiments are source-specific. The human gamma-containing alpha1/beta1 structure supplies independent support for the target complex membership. Preserve the original rat electronic transfer; neither native stoichiometry in every tissue nor equivalence of all FXYD family members is assumed.

Summary: Human structural experiments directly support pump-complex membership.

Reason: PMID:35803952 coexpressed untagged human FXYD2 AAG37906.1 with N-FLAG alpha1 and C-Strep beta1 in HEK293F cells, purified the complex and determined three cryo-EM states. This directly supports GO:0005890 membership. The deposited construct was not independently aligned to the current natural products, and the alpha-subunit gating/ion-binding mechanism is not assigned to FXYD2.

Summary: Retain gamma-subunit membership in the renal sodium/potassium pump.

Reason: The pig Q58K79 donor has IDA complex annotations from PMID:18075585. Its structural description identifies gamma with alpha/beta; independent human alpha1/beta1/FXYD2 cryo-EM structures directly establish the same complex class. Preserve the original ISS and both part_of renal cell/kidney atoms. No exact human isoform assignment or alpha catalytic activity is inferred from membership.

Summary: Retain the early TAS complex assertion with independent human support.

Reason: The authentic PMID:9048881 abstract reports human gamma-subunit cDNA and expression; its full paper was inaccessible and its historical short sequence is not equated with the current products. The complex-membership claim is independently established by later human alpha1/beta1/FXYD2 structures. Preserve the original TAS identifier and do not describe the early paper as a full structural or interaction assay that was read.

Summary: Specific retained sodium export and potassium import entail this broad transport term.

Reason: The IPR047282 electronic source is preserved. Retained GO:0036376 sodium ion export across plasma membrane and GO:1990573 potassium ion import across plasma membrane each have an official is_a-only ancestry path to GO:0006811. FXYD2 participates as the pump regulatory subunit, not as a free-standing ion pore. These specific transport contexts supply the relevant coverage, so the broader ion-transport term adds little independent information.

Summary: Specific retained pump-mediated cation movements cover this broad term.

Reason: Rat Q04679 has IDA cation-transport evidence from PMID:12626497, whose gamma constructs alter ouabain-sensitive rubidium uptake and pump sodium activation. Preserve the original rat and Ensembl donor identifiers. The separately retained sodium-export and potassium-import terms both entail GO:0006812 by verified is_a-only ancestry. This is a granularity judgment, not rejection of the rat experiment or a claim of isolated FXYD2 transport catalysis.

Summary: Retain the rat stress-associated growth effect as contextual.

Reason: The rat Q04679 source carries IMP support from PMID:15280368. In hyperosmotically challenged NRK-52E cells, gamma induction accompanies reduced pump Vmax and slowed growth; gamma-directed knockdown reverses much of both effects without changing alpha/beta abundance. This supports the propagated physiological context, while a dedicated human antiproliferative mechanism and downstream signaling are not established. The pump regulatory activity is the defining function.

Summary: Retain electrochemical-gradient maintenance at pump-complex scope.

Reason: PMID:24688018 studies Xenopus alpha1/beta3 pumps and conditional proton currents; its gamma helix is a structural-model element, not a direct human FXYD2 perturbation. Independent human FXYD2 regulation and complex-membership evidence makes a contribution to pump-dependent gradients biologically coherent. Retain the broad NAS process as contextual without presenting the cited paper as an isolated FXYD2 gradient-generation assay or assigning the alpha-subunit catalytic chemistry to gamma.

Summary: Plasma-membrane localization supplies the specific membrane coverage.

Reason: All original ARBA, orthology, InterPro and subcellular-location source identifiers are retained. GO:0005886 plasma membrane is retained elsewhere and has an official is_a-only ancestry path to GO:0016020. This is a term-granularity judgment, not a challenge to the experimentally supported membrane-spanning pump subunit.

Summary: Retain the renal basolateral localization inference.

Reason: The literal rat Q04679 donor carries IDA evidence from PMID:16757733. Selected original Results explicitly describe gamma/alpha1 colocalization in IMCD1 intercalated cells (Figure 2B) and IMCD2 cells (Figure 2C), alongside segment-specific basolateral gamma labeling. The separate high-resolution double-label association highlighted in the abstract concerns CHIF/FXYD4 and is not used as FXYD2 evidence. Retain the human orthology inference with the rat anatomical and antibody scope explicit; this is not an endogenous human experiment or proof that both current human products share every location.

Summary: Replace sodium-channel regulation with ATPase regulation.

Reason: The actual PTHR14132 tree/MSA places human P54710 below root PTN000364858, and the literal IBD matches all six source identifiers. The issue is functional type, not ancestry or donor count. Selected original mouse Fxyd2, dog/mouse FXYD1, rat FXYD4 and mouse/human FXYD5 assays measure ouabain-sensitive ATP hydrolysis, pump current or rubidium/sodium transport. GO:0017080 requires modulation of a sodium channel; GO:0099106 defines a channel by energy-independent pore-mediated diffusion. Human FXYD2 binds the Na,K-ATPase complex and alters its ion-affinity readouts. GO:0060590 captures that demonstrated regulatory role without claiming a loss of all possible channel effects.

Proposed replacements: ATPase regulator activity

Summary: The mouse orthology transfer describes pump regulation.

Reason: The literal mouse Q04646/ENSMUSP00000035429 source is retained. Mouse Fxyd2 knockout kidney assays in PMID:15755730 measure ouabain-sensitive ATP hydrolysis and altered ion affinity/thermal stability, not sodium-channel gating. Independent human FXYD2b pump measurements and human complex structures support ATPase regulator activity. This is a correction of activity class rather than a claim that mouse and human are unrelated or that the original experiment assayed the wrong gene.

Proposed replacements: ATPase regulator activity

Summary: A molecular-adaptor role is not independently established.

Reason: The pig Q58K79 donor has IDA GO:0030674 from PMID:18075585. Accessible structural descriptions show gamma association with the pump, but association alone does not establish the molecular bridging role required for an adaptor. The full donor evidence was unavailable, and the selected human structures were not used to infer an untested bridging mechanism. Preserve the original ISS, four renal/complex/input atoms and donor without substituting a confident negative conclusion.

Summary: Retain sodium export through the Na,K-ATPase regulatory complex.

Reason: The exact pig Q58K79 donor has IDA sodium-export annotations from the renal pump structure paper, including the source renal context. Independent human FXYD2b functional assays and human alpha1/beta1/gamma structures support participation of this auxiliary subunit in pump-mediated sodium export. FXYD2 regulates the transporter rather than catalyzing ion translocation independently. Preserve the original ISS and both cell/kidney occurs_in atoms; no new human tissue assay or current isoform specificity is inferred.

Summary: Use the specific sign-neutral process of Na,K-pump regulation.

Reason: The original IPR000272 mapping correctly identifies ion-transport regulation, but the established target is the sodium/potassium-exchanging ATPase. GO:1903406 specifically describes regulation of that transporter and has a verified is_a-only path to GO:0043269. Human FXYD2b experiments in PMID:33231612 measure conditional changes in pump ion affinity; human structures in PMID:35803952 establish its auxiliary-subunit membership. Rat gamma/CHIF expression experiments in PMID:12626497 independently distinguish their pump-regulatory effects. This replacement is more informative without committing to uniform activation or inhibition, and does not assign catalytic ion translocation to isolated FXYD2.

Proposed replacements: regulation of P-type sodium:potassium-exchanging transporter activity

Summary: Specific retained sodium export and potassium import entail transmembrane transport.

Reason: The pig Q58K79 donor has IDA transmembrane-transport evidence from PMID:18075585. Retained GO:0036376 and GO:1990573 each reach GO:0055085 through verified is_a-only ancestry. The broader term is true for the regulatory pump subunit but adds no separate transport role. Preserve this original ISS provenance and do not imply that the incompletely accessed pig paper was fully read.

Summary: Retain urinary-vesicle occurrence without current-isoform specificity.

Reason: The original human urine study reports FXYD2 in Table 1 with one unique peptide and seven spectra; the retained author database identifies historical NP_001671 with one peptide. Preserve the HDA annotation and urine extension. The accessible row has no peptide sequence, so the historical isoform-1 label does not map the detection to the current 66- or 64-residue products. This is positive vesicle-fraction occurrence rather than an established extracellular FXYD2 mechanism.

Summary: Retain hyperosmotic-salinity response as a rat-derived cellular context.

Reason: Rat Q04679 has IEP support from PMID:15280368. The original NRK-52E experiments explicitly vary osmolarity and demonstrate gamma induction, with knockdown-linked changes in pump activity and growth. This is meaningful stress-response evidence but does not identify FXYD2 as a primary osmosensor or establish equivalent endogenous human responses under every condition.

Summary: Replace the family channel-regulator mapping with ATPase regulation.

Reason: The IPR000272 mapping is retained as the source of this electronic assertion. The official ion-channel-regulator definition concerns direct modulation of an energy-independent channel. Human FXYD2 is physically present in alpha1/beta1 pump structures and changes Na,K-ATPase ion-affinity measurements in heterologous expression. ATPase regulator activity is therefore the supported functional class for this target; the family name alone neither establishes channel regulation nor proves that every family member lacks it.

Proposed replacements: ATPase regulator activity

Summary: The FXYD2-specific proton-transport contribution remains unresolved.

Reason: The selected original PMID:24688018 establishes conditional inward proton current through Xenopus alpha1/beta3 pumps and examines alpha1 mutations. A gamma helix appears in a structural model, but its role in the measured proton flux is not isolated. The paper also leaves physiological and regulatory implications open. Preserve this NAS process claim without assigning the alpha-subunit transport mechanism to human FXYD2 or calling the annotation false from incomplete target-specific evidence.

Summary: The specific positive-export inheritance is unresolved despite valid placement.

Reason: The actual human target path and literal PTN000364858 IBD with mouse FXYD1 MGI:MGI:1889273 and bovine FXYD1 Q3SZX0 are verified. PMID:17095720 supports PKC-dependent phospholemman enhancement of sodium extrusion, and PMID:12657675 supplies legitimate bovine donor pump evidence. Human PMID:33231612 Table 3 reports lower apparent intracellular sodium affinity for both FXYD1 and FXYD2: K0.5 values are 19.5 and 18.1 mM, respectively, versus 13.8 mM for alpha1/beta1 alone. The Discussion states that these differences disappear without intracellular potassium. Thus the shared baseline direction does not demonstrate FXYD2-specific divergence from the phosphorylation-dependent donor phenotype. An equivalent conditional positive-export mechanism in FXYD2 remains unresolved; the verified placement and donor evidence are preserved without an inferred ancestral loss or an unconditional inhibitory assertion.

Summary: Retain potassium import as a function of the regulated pump complex.

Reason: The exact pig Q58K79 donor carries IDA potassium-import evidence from PMID:18075585. Human FXYD2b alters the external-potassium dependence of Na,K-pump current, and human structures establish its gamma-subunit membership. This supports participation in complex-mediated potassium import, not independent gamma catalysis. Preserve the original ISS and both renal cell/kidney atoms without claiming new tissue or current-product specificity.