Evolution of Substrate Specificities in the P-Type ATPase Superfamily

Axelsen, Kristian B.; Palmgren, Michael G.

doi:10.1007/pl00006286

Cited by 841 publications

(802 citation statements)

References 47 publications

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“…The treasury of atomic structures that have accumulated over the last decade locates most of these motifs in the cytoplasmic domains, where they play key roles in ATP hydrolysis and the transduction of this hydrolysis into changes in protein conformation. By necessity, the transmembrane region is the locus of substrate binding and release; since the P-type ATPases have diverged in their substrate specificity [2], it is not surprising that the transmembrane region is variable between different classes of P-type ATPase. Nevertheless, the similarity in overall structure between members of different subfamilies shows clearly that the basic mechanisms by which they operate are the same, with substrates that are transported out of the cytoplasm loaded in the E1 conformation, and released at the luminal side in the E2P conformation.…”

Section: Common Mechanism Of Phosphorylation and Dephosphorylationmentioning

confidence: 99%

Outside of the box: recent news about phospholipid translocation by P4 ATPases

Stone

Williamson

2012

J Chem Biol

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The P4 subfamily of P-type ATPases includes phospholipid transporters. Moving such bulky amphipathic substrate molecules across the membrane poses unique mechanistic problems. Recently, three papers from three different laboratories have offered insights into some of these problems. One effect of these experiments will be to ignite a healthy debate about the path through the enzyme taken by the substrate. A second effect is to suggest a counterintuitive model for the critical substrate-binding site. By putting concrete hypotheses into play, these papers finally provide a foundation for investigations of mechanism for these proteins.Keywords P4 ATPase . Phospholipid transport . ATPase reaction cycleFraming the problem P-type ATPases are ATP-dependent ion transporters that derive their name from an aspartate that becomes transiently phosphorylated during the reaction cycle [17]. The structures of several members of the family have been determined at atomic resolution in the last decade, and they all have a large tripartite cytoplasmic domain and a small extracellular domain connected by six to ten transmembrane helices. The P4 subfamily of P-type ATPases was first defined in 1996, when the gene encoding an aminophospholipid translocase, ATP8A1, from bovine chromaffin granules [26] was found to be a relative of the previously identified yeast P-type ATPase, Drs2p [23]. P4 type ATPases are found in all eukaryotic organisms but not in prokaryotes. In vertebrates, there are 14 genes that encode P4 ATPases [9] while in yeast there are five; Drs2, Dnf1, Dnf2, Dnf3, and Neo1 [19]. Unlike the other subfamilies of P-type ATPases, which all transport simple ions, the only known substrates of the P4 ATPases are phospholipids.The transport mechanism of the P-type ATPases depends on sequential partial reactions of ATP hydrolysis-phosphorylation and dephosphorylation of the critical aspartic acid residue in the cytoplasmic P domain-and linked sequential conformational changes; coordination between chemical and conformational steps drives substrate across the membrane against a concentration gradient. The conformational changes link a binding pocket for the transported ion to either the cytoplasm (the E1 conformation) or the extracytoplasmic, or lumenal space (the E2 conformation). In the classic Post-Albers model [1,22], binding of ions in the E1 conformation enables phosphorylation to the E1P form; this form is conformationally unstable, and converts to the E2P conformation. Loss of ions into the luminal space from that conformation is the key to dephosphorylation to the E2 form. The latter is also conformationally unstable, and the enzyme thus converts back into the E1 conformation [1,22].There is a subtlety about this sequence of events which should be mentioned here, particularly as it applies to the E2P conformation. This latter designation must define two conformations; indeed, both have been crystallized in the case of the Ca-ATPase [15,16,27]. One is the form that releases the cytoplasmically bound ions into th...

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Section: Common Mechanism Of Phosphorylation and Dephosphorylationmentioning

confidence: 99%

Outside of the box: recent news about phospholipid translocation by P4 ATPases

Stone

Williamson

2012

J Chem Biol

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“…For plants, [10][11][12][13][14][15] NBD-lipid-labelled seedlings were ground, resuspended in 100 ml ½MS media and extracted twice as above. The lipid containing chloroform/methanol phase was collected, dried and resuspended in a small volume of chloroform before separation by thin-layer chromatography using chloroform/ethanol/water/triethylamine (30/35/7/35, v/v/v/v; ref.…”

Section: Analysis Of Nbd-lipid Metabolism In Yeast and Plantsmentioning

confidence: 99%

“…Whereas Neo1p is located in the early endosome 10 , Drs2p and Dnf3p occur in the trans-Golgi network 9 , and Dnf1p and Dnf2p are both located at the plasma membrane 9 . Likewise, several of the 14 P4-ATPases identified in humans 11 have been linked to phospholipid translocation and have been localized to the plasma membrane, the Golgi, and early endosomes 12 .…”

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confidence: 99%

A phospholipid uptake system in the model plant Arabidopsis thaliana

et al. 2015

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Plants use solar energy to produce lipids directly from inorganic elements and are not thought to require molecular systems for lipid uptake from the environment. Here we show that Arabidopsis thaliana Aminophospholipid ATPase10 (ALA10) is a P4-type ATPase flippase that internalizes exogenous phospholipids across the plasma membrane, after which they are rapidly metabolized. ALA10 expression and phospholipid uptake are high in the epidermal cells of the root tip and in guard cells, the latter of which regulate the size of stomatal apertures to modulate gas exchange. ALA10-knockout mutants exhibit reduced phospholipid uptake at the root tips and guard cells and are affected in growth and transpiration. The presence of a phospholipid uptake system in plants is surprising. Our results suggest that one possible physiological role of this system is to internalize lysophosphatidylcholine, a signalling lipid involved in root development and stomatal control.

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“…Na,K-ATPase, gastric H,K-ATPase and non-gastric H,KATPase form within the family of P-type ATPases a special subfamily (IIc) [1]. Like all other P-type ATPases, its members have a catalytic subunit (α) with a molecular mass around 100 kDa.…”

Section: Introductionmentioning

confidence: 99%

“…The phylogenic distance between the catalytic subunits of Na,K-ATPase, gastric H,K-ATPase and nongastric H,K-ATPase is about similar. There are three genes that code for β-subunits of Na,K-ATPase (β [1][2][3] ) and one for the β-subunit of gastric H,K-ATPase (β HK ). The nongastric H,K-ATPase has no own β-subunit but most likely uses the β 1 -subunit of Na,K-ATPase [2][3][4].…”

Section: Introductionmentioning

confidence: 99%