Shadows of an Absent Partner

Corradi, Gerardo R.; Pinto, Felicitas de Tezanos; Mazzitelli, Luciana R.; Adamo, Hugo P.

doi:10.1074/jbc.m112.363465

Cited by 17 publications

(19 citation statements)

References 40 publications

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“…cerevisiae P5-type ATPases Spf1p and Ypk9p contain the highly conserved P-type ATPase sequence motifs required for transport. Autophosphorylation was previously reported for Spf1p, which takes place on the Asp487 residue in the autophosphorylation motif [ 56 ]. To produce Ypk9p protein for biochemical assays we purified 10xHis-FLAG tagged versions of Ypk9p and the catalytic dead mutant Ypk9p (D781N) from overexpression in yeast ( Fig 3E and 3F , and S3 Fig ) and could demonstrate that Ypk9p undergoes autophosphorylation, which is impaired by a mutation of the catalytic Asp781 residue in the P-type motif for autophosphorylation ( Fig 3F ).…”

Section: Resultsmentioning

confidence: 99%

Parkinson disease related ATP13A2 evolved early in animal evolution

et al. 2018

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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.

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Section: Resultsmentioning

confidence: 99%

Parkinson disease related ATP13A2 evolved early in animal evolution

et al. 2018

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“…Spontaneous auto-phosphorylation has already been observed for the yeast P5A ATPase Spf1p and the plant P5A ATPase HvP5A1 (Corradi et al, 2012; Sorensen et al, 2012), but so far it remains unclear whether P5B-ATPases such as ATP13A2 also form a phospho-intermediate.…”

Section: The Family Of P-type Atpasesmentioning

confidence: 99%

Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders

Veen

Sørensen

Holemans

et al. 2014

Front. Mol. Neurosci.

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Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na+/K+-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.

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“…A distinctive characteristic of P-type ATPases is the coupling of the transport process with the formation and decomposition of an aspartyl-phosphoenzyme (EP) during each transport cycle [24,25]. In agreement with predictions based on the primary amino acid sequences, all P5A ATPases characterized so far have been shown to hydrolyze ATP and to form an EP phosphoenzyme intermediate [16,[26][27][28]. While EP formation seems to proceed with Mg 2+ as the only required ion, lower levels of EP were detected in the presence of Ca 2+ , an observation that was taken to indicate that Spf1p is possibly regulated by Ca 2+ [26,27].…”

Section: Introductionmentioning

confidence: 64%

“…While EP formation seems to proceed with Mg 2+ as the only required ion, lower levels of EP were detected in the presence of Ca 2+ , an observation that was taken to indicate that Spf1p is possibly regulated by Ca 2+ [26,27]. Intriguingly, Ca 2 + -dependent EP dephosphorylation did not require the endogenous phosphatase activity of the enzyme [26] and the ATPase activity of Spf1p was only marginally affected by Ca 2+ [16,19,28].…”

Section: Introductionmentioning

confidence: 95%

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Reduction of the P5A-ATPase Spf1p phosphoenzyme by a Ca2+-dependent phosphatase

et al. 2020

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P5 ATPases are eukaryotic pumps important for cellular metal ion, lipid and protein homeostasis; however, their transported substrate, if any, remains to be identified. Ca 2+ was proposed to act as a ligand of P5 ATPases because it decreases the level of phosphoenzyme of the Spf1p P5A ATPase from Saccharomyces cerevisiae. Repeating previous purification protocols, we obtained a purified preparation of Spf1p that was close to homogeneity and exhibited ATP hydrolytic activity that was stimulated by the addition of CaCl 2. Strikingly, a preparation of a catalytically dead mutant Spf1p (D 487 N) also exhibited Ca 2+-dependent ATP hydrolytic activity. These results indicated that the Spf1p preparation contained a copurifying protein capable of hydrolyzing ATP at a high rate. The activity was likely due to a phosphatase, since the protein i) was highly active when pNPP was used as substrate, ii) required Ca 2+ or Zn 2+ for activity, and iii) was strongly inhibited by molybdate, beryllium and other phosphatase substrates. Mass spectrometry identified the phosphatase Pho8p as a contaminant of the Spf1p preparation. Modification of the purification procedure led to a contaminant-free Spf1p preparation that was neither stimulated by Ca 2+ nor inhibited by EGTA or molybdate. The phosphoenzyme levels of a contaminant-free Spf1p preparation were not affected by Ca 2+. These results indicate that the reported effects of Ca 2+ on Spf1p do not reflect the intrinsic properties of Spf1p but are mediated by the activity of the accompanying phosphatase.

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Shadows of an Absent Partner

Cited by 17 publications

References 40 publications

Parkinson disease related ATP13A2 evolved early in animal evolution

Parkinson disease related ATP13A2 evolved early in animal evolution

Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders

Reduction of the P5A-ATPase Spf1p phosphoenzyme by a Ca2+-dependent phosphatase

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