3.A.3.10.19
Mn²⁺-exporting ATPase, ATP13A1 of 1204 aas.  Defects cause Mn²⁺-dependent neurological disorders.  Orthologous to the yeast Mn²⁺-ATPase, Spf1 (Cohen et al. 2013). It is present in the endoplasmic reticulum while the other P5 ATPases, A2 - A5, are in overlapping compartments of the endosomal system (Sørensen et al. 2018). It complements the yeast ER ATPase, SPF1 (TC#3.A.3.10.3) although ATP13A2 - 5 do not, and unlike these latter proteins, it seems to have 12 (rather than 10) TMSs, with the two extra ones in an N-terminal domain (Sørensen et al. 2018). ATP13A1 (Spf1 in yeast) directly interacts with the TMSs of mitochondrial tail-anchored proteins (McKenna et al. 2020). P5A-ATPase mediates the extraction of mistargeted proteins from the endoplasmic reticulum (ER). Cryo-electron microscopy structures of Saccharomyces cerevisiae Spf1 (TC# 3.A.3.10.3) revealed a large, membrane-accessible substrate-binding pocket that alternately faced the ER lumen and cytosol and an endogenous substrate resembling an alpha-helical TMS. Thus, the P5A-ATPase can dislocate misinserted hydrophobic helices flanked by short basic segments from the ER. TMS dislocation by the P5A-ATPase establishes an additional class of P-type ATPase substrates and may correct mistakes in protein targeting or topogenesis (McKenna et al. 2020). It has been designated as a transmembrane islocase (Dederer and Lemberg 2021). It was initially thought to mediate manganese transport (Cohen et al. 2013). However, it was later shown to specifically bind moderately hydrophobic TMSs with short hydrophilic lumenal domains that misinsert into the endoplasmic reticulum (McKenna et al. 2020). The P5A-ATPase extracts mistargeted or mis-inserted TMSs from the ER membrane for protein quality control, while the P5B-ATPases mediate export of polyamines from late endo-/lysosomes into the cytosol (Sim and Park 2023). ATP13A1 prevents ERAD of folding-competent mislocalized and misoriented proteins (McKenna et al. 2022). Thus, the P5A-ATPase ATP13A1 prevents the accumulation of mislocalized and misoriented proteins, which are eliminated by different ER-associated degradation (ERAD) pathways in mammalian cells. Without ATP13A1, mitochondrial tail-anchored proteins mislocalize to the ER through the ER membrane protein complex and are cleaved by signal peptide peptidase for ERAD. ATP13A1 also facilitates the topogenesis of a subset of proteins with an N-terminal TMS or a signal sequence that should insert into the ER membrane with a cytosolic N terminus. Without ATP13A1, such proteins accumulate in the wrong orientation and are targeted for ERAD by distinct ubiquitin ligases. Thus, ATP13A1 prevents ERAD of diverse proteins capable of proper folding (McKenna et al. 2022).