| Aspect | Summary |
|---|---|
| Identity | • ATP13A1 matches human UniProt Q9HD20 and is the ER-resident P5A-ATPase.
• It is the only P5A ATPase in human/mouse and is orthologous to yeast Spf1 and worm CATP-8. (pqac-00000001, pqac-00000008, pqac-00000013) |
| Localization | • Predominantly localized to the endoplasmic reticulum membrane.
• Functions at the ER in membrane protein targeting, topology correction, and quality control. (pqac-00000001, pqac-00000004, pqac-00000008) |
| Primary molecular function & substrate | • Best-supported function is ATP-dependent dislocation/extraction of transmembrane helices or polypeptide segments from the ER membrane, not classical ion pumping.
• Substrates include mistargeted mitochondrial tail-anchored proteins, misinserted terminal helices, and some atypical or misoriented signal sequences.
• Supported direction is ER membrane to cytosolic/soluble pool during extraction. (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000007) |
| Mechanism & structure | • Cryo-EM studies show a large membrane-accessible substrate pocket/cleft that alternates between cytosol- and lumen-facing states in a canonical P-type ATPase cycle.
• Substrate preference favors moderately hydrophobic helices with short luminal hydrophilic or basic flanks; large luminal domains are disfavored.
• Recent structures highlight an electronegative pocket and a Plug-domain/gating element; residues such as E492/E496 and L499 contribute to substrate engagement. (pqac-00000004, pqac-00000005, pqac-00000007, pqac-00000008, pqac-00000009) |
| Key experimental systems & assays | • Core systems include human ATP13A1 knockout cells, yeast Spf1, and worm CATP-8.
• Evidence comes from site-specific crosslinking, cell-free reconstitution and extraction assays, proteomics, immunofluorescence mislocalization assays, and cryo-EM.
• Catalytic dependence was shown by rescue with WT but not phosphorylation-site mutants such as D533A or D533N. (pqac-00000001, pqac-00000005, pqac-00000006, pqac-00000007, pqac-00000010) |
| Phenotypes & pathways (protein targeting QC, MAVS antiviral, MR1 antigen presentation) | • Protein targeting QC: ATP13A1 loss causes ER accumulation or mislocalization of mitochondrial tail-anchored proteins and broader ER proteostasis defects.
• MAVS antiviral pathway: deficiency compromises MAVS stability, IRF3 activation, and antiviral responses; myeloid-specific knockout mice are more susceptible to RNA virus infection.
• MR1 antigen presentation: ATP13A1 knockout lowers MR1 protein and surface expression and selectively impairs MR1-mediated MAIT-cell activation with little effect on classical MHC I. (pqac-00000001, pqac-00000012, pqac-00000013, pqac-00000014, pqac-00000015, pqac-00000019) |
| Key recent developments 2024-2025 | • 2024 structural work strengthened the model that P5A-ATPases transport polypeptide or helix cargo through a membrane-spanning cleft and identified a possible Plug-domain role.
• 2025 work proposed that human ATP13A1 can transfer atypical signal-sequence substrates to SEC61, extending its role to substrate-specific translocation proofreading.
• Recent expert perspectives place ATP13A1 among ER accessory factors that improve fidelity of membrane protein insertion and organelle identity. (pqac-00000002, pqac-00000007, pqac-00000008) |
| Open questions | • Whether ATP13A1 acts only as a dislocase or can also directly support insertion, secretion, or topogenesis for selected substrates remains unresolved.
• The full human substrate spectrum, selection rules, and integration with GET3, SEC61, EMC, ERAD, and mitochondrial targeting pathways are still being defined.
• It remains unclear which immune and developmental phenotypes are direct client-specific effects versus secondary consequences of ER homeostasis failure. (pqac-00000002, pqac-00000003, pqac-00000008) |
*Table: This table summarizes the current functional annotation of human ATP13A1 (UniProt Q9HD20), including identity, localization, molecular function, mechanism, experimental evidence, phenotypes, and recent advances. It provides a compact evidence map for the major claims about ATP13A1.*