Abstract
Several human P5-type transport ATPases are implicated in neurological disorders, but little is known about their physiological function and properties. Here, we investigated the relationship between the five mammalian P5 isoforms ATP13A1-5 in a comparative study. We demonstrated that ATP13A1-4 isoforms undergo autophosphorylation, which is a hallmark P-type ATPase property that is required for substrate transport. A phylogenetic analysis of P5 sequences revealed that ATP13A1 represents clade P5A, which is highly conserved between fungi and animals with one member in each investigated species. The ATP13A2-5 isoforms belong to clade P5B and diversified from one isoform in fungi and primitive animals to a maximum of four in mammals by successive gene duplication events in vertebrate evolution. We revealed that ATP13A1 localizes in the endoplasmic reticulum (ER) and experimentally demonstrate that ATP13A1 likely contains 12 transmembrane helices. Conversely, ATP13A2-5 isoforms reside in overlapping compartments of the endosomal system and likely contain 10 transmembrane helices, similar to what was demonstrated earlier for ATP13A2. ATP13A1 complemented a deletion of the yeast P5A ATPase SPF1, while none of ATP13A2-5 could complement either the loss of SPF1 or that of the single P5B ATPase YPK9 in yeast. Thus, ATP13A1 carries out a basic ER function similar to its yeast counterpart Spf1p that plays a role in ER related processes like protein folding and processing. ATP13A2-5 isoforms diversified in mammals and are expressed in the endosomal system where they may have evolved novel complementary or partially redundant functions. While most P5-type ATPases are widely expressed, some P5B-type ATPases (ATP13A4 and ATP13A5) display a more limited tissue distribution in the brain and epithelial glandular cells, where they may exert specialized functions. At least some P5B isoforms are of vital importance for the nervous system, since ATP13A2 and ATP13A4 are linked to respectively Parkinson disease and autism spectrum disorders.
Highlights
P-type ATPases are intrinsic membrane proteins that couple the hydrolysis of ATP to the active transport of substrates over biological membranes [1]
To explore the relationship between the mammalian P5-type ATPase isoforms, we performed a phylogenetic analysis of 146 animal P5 ATPase sequences belonging to 22 different phyla across 43 individual organisms
The sequences were aligned and subsequently subjected to a phylogenetic analysis based on both the Bayesian inference and maximum likelihood methods, which provides superior statistics as compared to previous phylogenetic approaches that were used to compare the P5-ATPases in eukaryotes [44, 53]
Summary
P-type ATPases are intrinsic membrane proteins that couple the hydrolysis of ATP to the active transport of substrates over biological membranes [1]. Various substrates for the P5 ATPases were proposed, ranging from ion transport (e.g. Ca2+, Mg2+, Mn2+ or Zn2+) to polyamines, sterols or other lipids, but conclusive evidence has not yet been presented [5,6,7,8,9,10,11,12,13,14,15,16,17,18] Despite their elusive molecular function, two of the five human P5 ATPases, i.e. ATP13A2 and ATP13A4, have attracted considerable interest as they are implicated in neurological disorders. ATP13A2 protects against mitochondrial stress [7, 14, 15, 34, 35], e.g. induced by complex I inhibition [4, 36, 37]
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