ATP13A1 notes

2026-06-03 - Proteostasis PN review pass

• just fetch-gene human ATP13A1 created the review stub, UniProt record, GOA table, cached publications, Reactome entries, and PANTHER family data. Falcon deep research was attempted with perplexity-lite fallback; the wrapper reported a Falcon timeout after 600 seconds and the fallback failed with a Perplexity quota/401 error, but ATP13A1-deep-research-falcon.md was written and incorporated into this review.
• ATP13A1 is best treated as an ER membrane P5A-type P-type ATPase whose direct function is ATP-dependent transmembrane-helix dislocation. McKenna et al. report that ATP13A1 directly interacts with mitochondrial tail-anchored protein transmembrane segments and that "ATP13A1 mediates ATP-dependent removal of a mitochondrial TM from the ER" [PMID:32973005 The endoplasmic reticulum P5A-ATPase is a transmembrane helix dislocase].
• The same paper supports the biological-process annotation to extraction of mislocalized proteins from the ER membrane: ATP13A1 knockout increased ER/secretory-pathway mislocalization of mitochondrial tail-anchored reporters, rescue required wild-type but not catalytic-dead ATP13A1, and the authors conclude a quality-control role in "removing misinserted terminal hydrophobic helices from the ER" PMID:32973005.
• The later MTCH2 study independently uses ATP13A1 as the ER-side dislocase in the mitochondrial tail-anchored protein targeting system, stating that MTCH2 depletion effects were enhanced by depleting "ATP13A1 (19), an ER dislocase for mislocalized mitochondrial TAs" [PMID:36264797 MTCH2 is a mitochondrial outer membrane protein insertase].
• ER membrane localization is supported by the early human ATP13A1 work: "immunohistochemistry of HeLa cells reveals a reticular pattern surrounding the nucleus of the cell as would be expected from an ER resident protein" [PMID:24392018 The yeast p5 type ATPase, spf1, regulates manganese transport into the endoplasmic reticulum].
• Manganese/cation transport annotations should be removed or modified conservatively. Cohen et al. linked yeast Spf1 and human ATP13A1 to manganese-dependent cellular phenotypes, but they explicitly state that their results "can not prove that Spf1 is the direct transporter of Mn2+" PMID:24392018. McKenna et al. later found a large membrane-accessible substrate pocket and state that its structure argues "against the idea that the P5A-ATPase transports cations" PMID:32973005.
• Reactome:R-HSA- PMID:5692462 still asserts "ATP13A1 transports Mn2+ from cytosol to ER lumen"; this appears to reflect the superseded 2013 interpretation and should not drive GO review decisions for ATP13A1 molecular function.

PN projection decision

• The PN projection report has one candidate addition for ATP13A1: GO:0015031 protein transport, propagated from ER proteostasis | Protein transport | Removal of misinserted transmembrane proteins.
• Working curation conclusion: do not add the broad parent GO:0015031 protein transport candidate. ATP13A1 already has the narrower, directly supported GO:0140567 membrane protein dislocase activity and GO:0140569 extraction of mislocalized protein from ER membrane annotations, and adding protein transport would be less informative than the reviewed dislocase/extraction terms.

2026-09-20 IBA full-gene re-review

All 29 annotation rows were reassessed; source isoform metadata remains intact. Broad membrane, nucleotide binding, transport and P-type-transporter annotations were restored. Live GO:0140358 defines the phosphorylated-aspartate transport cycle and does not require an ion substrate. Ion-specific correction remains supported by the actual Spf1 substrate-pocket geometry and ATP13A1 extraction experiment (PMID:32973005), not merely by discovery of a different primary function. PMID:24392018 expressly states "can not prove that Spf1 is the direct transporter of Mn2+". Calcium homeostasis is separately retained as a non-core inherited process; no target-specific loss was shown. Generic protein binding was removed as uninformative without disputing interactions.

The existing hypothesis report kgap-atp13a1-dislocase-vs-topogenesis was read substantively and incorporated. Its central point that the old hypothesis "draws a false dichotomy regarding biological function" is supported by primary evidence: PMID:36283413 establishes productive topogenesis and protection from ERAD, PMID:38723633 describes human ABCG2 folding, and PMID:40498833 supports atypical signal-sequence correction coupled to SEC61. Description, activity reviews and core synthesis now include both quality control and productive topogenesis. Caveat: the 2025 cryo-EM structures are of human ATP13A1, not a resolved ATP13A1-SEC61 handoff complex; the paper states "It remains to be characterized how ATP13A1 engages SEC61". PMID:42208892 measures purified yeast Spf1 substrate-stimulated ATPase activity, not complete reconstituted dislocation: "ATP hydrolysis in this in vitro system remains an indirect readout of substrate engagement." The report's stronger reconstitution framing is not adopted. MAVS studies PMID:37043539 and PMID:35543156 provide client context but do not require manufacturing new process annotations.

Original ion-IBA sources are PTN001944130 (GO:0019829) and PTN000643319 (GO:0015662), recovered from GOA WITH/FROM. Current PTHR45630 PAINT retains protein dislocation, calcium homeostasis and membrane/transport but lacks those ion assertions. This version difference is documented without inventing the reason for change. Calcium mechanistic follow-up is human expert work; the existing report already flags it, so no duplicate report requested.

Recovery review consistency follow-up (2026-09-22)

Restored readable identifiers in manual prose. Where applicable, reconciled AP3M2 reference notes with the retained contextual claim, removed unrelated PIK3C3 support from unresolved projections, separated PIK3C3 aspect-specific reasons, and documented the surviving/renamed ATG14 membrane term. Source assertion fields and verbatim quotations are unchanged.