ATP8A2

Summary: Golgi membrane is a supported functional location.

Reason: The SL-0134 mapping agrees with the integral membrane protein architecture and CDC50A-dependent Golgi localization. The evidence is a location assignment; a human Golgi lipid-flux experiment is not claimed.

Summary: ATP binding is the informative nucleotide-binding specificity.

Reason: IPR023299 supports a nucleotide-binding fold, while ATP-dependent catalysis identifies the substrate nucleotide. Retain the domain-derived source and refine the reviewed function to ATP binding.

Proposed replacements: ATP binding

Summary: Magnesium binding is a catalytic cofactor property.

Reason: The IPR006539 inference is consistent with the Mg-dependent P-type ATPase cycle and conserved cofactor annotations in UniProt. This is not an independent human metal-binding titration or a second core function.

Summary: ATP8A2 associates with CDC50A as the catalytic subunit of a heteromeric flippase.

Reason: The original IPI assertion names CDC50A/TMEM30A (Q9NV96), and the cited abstract describes ATP8A2 variants coexpressed with this accessory subunit. Independent assembly experiments establish the ATP8A2–CDC50A α/β complex and support refinement to protein heterodimerization activity. PMID:21454556 used bovine ATP8A2 and bovine CDC50A for the dual-purification/reconstitution experiments; endogenous human CDC50A association was also detected with expressed bovine ATP8A2. This is conserved complex-assembly support, not a claim that the original abstract contains a human 1:1 stoichiometry measurement. Preserve the original IPI source and named partner. Complex membership and heterodimerization express related but distinct CC and MF assertions.

Proposed replacements: protein heterodimerization activity

Summary: ATP binding is an intrinsic facet of flippase catalysis.

Reason: The IPR001757/IPR006539 assignment agrees with ATP-driven transport and the purified human-complex ATPase measurements. It belongs to the same transport mechanism rather than a separate ATP-binding core.

Summary: Endosomal membrane is more precise than the whole endosome.

Reason: The P98200 orthology route is supported by donor localization in Rab11-positive compartments. ATP8A2 is an integral membrane pump, so refine the compartment to endosome membrane without relabeling the donor experiment as human IDA.

Proposed replacements: endosome membrane

Summary: CDC50A coexpression supports Golgi localization.

Reason: Retain this experimentally curated organelle location. The cited abstract and selected original localization Results support Golgi targeting; the inspected Methods paragraph does not independently establish the ATP8A2 construct species. The IDA row is retained at the experimentally curated organelle resolution; this does not dispute that the multipass pump occupies a membrane. The electronic counterpart is refined using independent membrane topology.

Summary: The Golgi membrane is the appropriate pump compartment.

Reason: The mouse orthology-derived Golgi assignment agrees with donor localization and independent heterologous localization. Refine this electronic organelle-level row to the membrane occupied by the multipass pump.

Proposed replacements: Golgi membrane

Summary: A trans-Golgi context is compatible with the conserved flippase.

Reason: Retain the considered PTN008394225 inference, corroborated by Golgi/endosomal localization of the ATP8A2-CDC50A complex. The exact PAINT tree and compartment-specific human activity assay were not inspected; the two yeast evidence entries are not grounds to reject the ancestral inference.

Summary: Plasma-membrane flippase activity is supported independently.

Reason: The PTN000642368 ancestral inference is consistent with human ATP8A2 cellular activity. Q9NTI2 appearing among descendant evidence is legitimate target experimental grounding, not circularity. No full PAINT reconstruction is claimed.

Summary: Curated plasma-membrane localization matches independent experiments.

Reason: GO_REF:0000052 is an immunofluorescence curation route. Its original image was not re-read, but the same human location is independently supported by the ATP8A2/CDC50A study; retain curator deference without inventing image-specific details.

Summary: The cited study supports plasma-membrane localization.

Reason: The normal abstract and selected original localization text describe CDC50A-dependent ER exit and arrival at the cell surface. Retain the original IDA and its localization scope, without claiming transport was measured by this particular experiment.

Summary: Human ATP8A2 reaches the plasma membrane with CDC50A.

Reason: The cited human-transporter study directly links CDC50A-dependent cell-surface localization with flippase function. The human protein was assayed in heterologous cells; this is not a native human tissue localization survey.

Summary: The cell-surface location mapping is well supported.

Reason: SL-0039 agrees with direct human ATP8A2/CDC50A plasma-membrane observations. Preserve its electronic provenance rather than substituting an experimental evidence code.

Summary: The ML-1 growth-control phenotype is a restricted cellular context.

Reason: Original human tumor-cell antisense experiments and a nude-mouse endpoint support the cited association. The partial historical clone and this model do not establish a universal tumor-suppressor mechanism or the physiological core activity of every ATP8A2 isoform.

Summary: Endosome membrane is a plausible conserved operating location.

Reason: SL-0100 agrees with the multipass architecture and the donor endosomal-localization route. Preserve the mapping and its orthology limitation; no new human endogenous endosomal assay is asserted.

Summary: The endosomal-membrane similarity transfer is supported.

Reason: P98200 is mouse Atp8a2, with a concrete localization route. Retain the ISS assignment as conserved membrane context rather than upgrading it to human experimental evidence.

Summary: Retinal degeneration does not establish retinal lamination.

Reason: GO:0010842 denotes layer formation. The mouse study reports normal early wl/wl retinal appearance followed by photoreceptor loss and thinning. This electronic developmental specificity exceeds that endpoint, without denying retinal physiology or asserting that the donor curation used no other evidence.

Summary: Neurite outgrowth is a supported downstream neuronal context.

Reason: The donor route includes ATP8A2 overexpression in PC12 cells and primary rat hippocampal cultures. The complete official abstract supports outgrowth, while construct species and full Methods remain unresolved. Retain the orthology-derived context outside the catalytic core.

Summary: Auditory responsiveness is a supported mouse-derived phenotype.

Reason: The donor study measured auditory brainstem thresholds in mutant mice. Retain this physiological context separately from the membrane transport core and do not describe it as a human auditory assay.

Summary: Specific Golgi and endosomal membranes replace a broad system label.

Reason: ARBA00028953 supplies a broad endomembrane assignment. Independent localization and integral-membrane architecture support Golgi membrane and endosome membrane as the informative reviewed locations.

Proposed replacements: Golgi membrane endosome membrane

Summary: Aminophospholipid flippase activity captures the coupled transport function.

Reason: The mouse orthology mapping agrees with inward PS transport and the conserved lower PE activity. GO:0015247 describes exoplasmic-to-cytoplasmic ATP-dependent flipping; the PS and PE evidence need not imply equal rates or bidirectional transport.

Summary: Intrabilayer aminophospholipid translocation is more specific than transport.

Reason: The IPR006539 source points to a P4-ATPase. Existing substrate-specific and direct transport evidence support moving aminophospholipids between membrane leaflets, rather than leaving the annotation at unrestricted phospholipid transport.

Proposed replacements: aminophospholipid translocation

Summary: Defined operating membranes are more informative than membrane alone.

Reason: The integrated ARBA/domain/subcellular/orthology sources establish a membrane protein. Independent evidence supports plasma, Golgi and endosomal membranes; this refinement is biological interpretation, not a claim that every component source measured each location.

Proposed replacements: plasma membrane Golgi membrane endosome membrane

Summary: ATP hydrolysis powers the lipid-transport cycle.

Reason: The IPR001757 inference is directly corroborated by purified human ATP8A2-complex ATPase measurements. Hydrolysis is a mechanism facet of the flippase, not a separate generic enzyme core.

Summary: Adult auditory degeneration does not establish embryonic inner-ear morphogenesis.

Reason: GO:0042472 is under embryonic morphogenesis. The inspected mouse endpoint is spiral-ganglion loss with preserved organ of Corti and hair cells. Flag the electronic developmental specificity while retaining hearing-response context; no universal absence of developmental roles is claimed.

Summary: Aminophospholipid translocation refines the conserved process.

Reason: PTN000642368 supports an ancestral lipid-translocation process. Refine its broad substrate class using target-specific PS activity and conserved PE transport, without rejecting the PAINT placement or changing the original IBA tuple. The broader PAINT assertion remains biologically sound. This human review selects independently supported substrate specificity under the requested specificity rule; duplicate replacement terms on distinct source rows are allowed. No full PAINT tree reconstruction or narrower ancestral-node claim is made.

Proposed replacements: aminophospholipid translocation

Summary: Neuronal development is retained as a contextual ancestral inference.

Reason: The old mouse donor abstract emphasizes degeneration and does not by itself revalidate PTN002787599. Later neurite-outgrowth evidence independently supports a developmental context. Retain the considered IBA outside the catalytic core; neither donor count nor missing tree inspection is treated as evidence of misplacement.

Summary: Visual responsiveness is a supported sensory consequence.

Reason: The mouse donor study measured reduced retinal electrical responses. Retain the physiological association as non-core; ATP8A2 is not thereby established as a photopigment or the molecular light detector.

Summary: Neurofilament organization is supported in the mouse disease context.

Reason: The original donor study documents phosphorylated-neurofilament redistribution in affected neurons. This supports the existing contextual transfer, but not a direct cytoskeletal enzyme or structural-filament core.

Summary: The inspected assay supports carrying out lipid translocation.

Reason: GO:0061092 is positive regulation of another process, not simply a parent of translocation. The traced donor experiment measures ATP8A2-dependent lipid uptake and catalytic controls. Replace the regulatory role with the direct aminophospholipid-translocation process already represented elsewhere; this is a role correction, not a NEW assertion.

Proposed replacements: aminophospholipid translocation

Summary: PE flipping is supported as the weaker conserved substrate activity.

Reason: The C7EXK4 transfer is bovine. Bovine ATP8A2/CDC50A proteoliposomes directly transported PE less efficiently than PS. Human PE-stimulated ATP turnover is corroboration, not a substitute for flux. Preserve ISS and do not infer outward PE transport from the inconsistent raw Rhea entry.

Summary: The PS transport direction is inward, not outward.

Reason: GO:0090556 means cytoplasmic-to-exoplasmic flopping; ATP8A2 transports PS in the reverse direction. The RHEA:38567 mapping conflicts with the actual GO direction. Preserve that machine tuple and replace its reviewed function with GO:0140346. This corrects a direction mapping, not evidence of a bidirectional pump.

Proposed replacements: phosphatidylserine flippase activity

Summary: The ancestral lipid-carrier function can be refined to inward aminophospholipid flipping.

Reason: PTN000642368 supports the broader ATP-coupled intramembrane mechanism. Target-specific and conserved substrate evidence justify the flippase specificity without arguing against the ancestral placement or claiming all family members share this specificity. The broader PAINT assertion remains biologically sound. This human review selects independently supported substrate specificity under the requested specificity rule; duplicate replacement terms on distinct source rows are allowed. No full PAINT tree reconstruction or narrower ancestral-node claim is made.

Proposed replacements: aminophospholipid flippase activity

Summary: The domain and EC mechanism can be given substrate and direction specificity.

Reason: IPR006539 and EC:7.6.2.1 describe the broader lipid-translocating ATPase. Refine this electronic row to aminophospholipid flippase using the independently supported inward PS/PE transport mechanism.

Proposed replacements: aminophospholipid flippase activity

Summary: Aminophospholipid translocation is the direct transport process.

Reason: The bovine C7EXK4 ISS route is experimentally grounded and agrees with human PS transport. ATP8A2 itself performs the transport step; no extra developmental or vesicle-biogenesis assertion is manufactured from its necessity.

Summary: PS flippase is the principal directly corroborated activity.

Reason: The original bovine ISS provenance remains unchanged. Human cellular PS transport independently supports the same inward activity, while PS is a stronger substrate than PE in the characterized orthologous complex.

Summary: The ATP8A2-CDC50A complex is a supported catalytic assembly.

Reason: ARBA00090460 agrees with the experimentally established catalytic alpha-subunit/accessory beta-subunit complex. Membership does not imply that ATP8A2 lacks its own catalytic molecular function.

Summary: The cited interaction supports phospholipid-translocating complex membership.

Reason: The original IPI assignment and normal abstract identify the CDC50A-associated ATP8A2 complex. Preserve the association evidence separately from a direct transport assay and from unsupported universal isoform equivalence.