Dataset Information

Nematode phospholipid metabolism: an example of closing the genome-structure-function circle.

ABSTRACT: Parasitic nematodes that infect humans, animals, and plants cause health problems, livestock and agricultural losses, and economic damage worldwide and are important targets for drug development. The growing availability of nematode genomes supports the discovery of new pathways that differ from host organisms and are a starting point for structural and functional studies of novel antiparasitic targets. As an example of how genome data, structural biology, and biochemistry integrate into a research cycle targeting parasites, we summarize the discovery of the phosphobase methylation pathway for phospholipid synthesis in nematodes and compare the phosphoethanolamine methyltransferases (PMTs) from nematodes, plants, and Plasmodium. Crystallographic and biochemical studies of the PMTs in this pathway provide a foundation that guides the next steps that close the genome-structure-function circle.

SUBMITTER: Lee SG

PROVIDER: S-EPMC4040950 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Nematode phospholipid metabolism: an example of closing the genome-structure-function circle.

Lee Soon Goo SG Jez Joseph M JM

Trends in parasitology 20140328 5

Parasitic nematodes that infect humans, animals, and plants cause health problems, livestock and agricultural losses, and economic damage worldwide and are important targets for drug development. The growing availability of nematode genomes supports the discovery of new pathways that differ from host organisms and are a starting point for structural and functional studies of novel antiparasitic targets. As an example of how genome data, structural biology, and biochemistry integrate into a resea ...[more]

PMID: 24685202

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Project description:P4-ATPases comprise a family of P-type ATPases that actively transport or flip phospholipids across cell membranes. This generates and maintains membrane lipid asymmetry, a property essential for a wide variety of cellular processes such as vesicle budding and trafficking, cell signaling, blood coagulation, apoptosis, bile and cholesterol homeostasis, and neuronal cell survival. Some P4-ATPases transport phosphatidylserine and phosphatidylethanolamine across the plasma membrane or intracellular membranes whereas other P4-ATPases are specific for phosphatidylcholine. The importance of P4-ATPases is highlighted by the finding that genetic defects in two P4-ATPases ATP8A2 and ATP8B1 are associated with severe human disorders. Recent studies have provided insight into how P4-ATPases translocate phospholipids across membranes. P4-ATPases form a phosphorylated intermediate at the aspartate of the P-type ATPase signature sequence, and dephosphorylation is activated by the lipid substrate being flipped from the exoplasmic to the cytoplasmic leaflet similar to the activation of dephosphorylation of Na(+)/K(+)-ATPase by exoplasmic K(+). How the phospholipid is translocated can be understood in terms of a peripheral hydrophobic gate pathway between transmembrane helices M1, M3, M4, and M6. This pathway, which partially overlaps with the suggested pathway for migration of Ca(2+) in the opposite direction in the Ca(2+)-ATPase, is wider than the latter, thereby accommodating the phospholipid head group. The head group is propelled along against its concentration gradient with the hydrocarbon chains projecting out into the lipid phase by movement of an isoleucine located at the position corresponding to an ion binding glutamate in the Ca(2+)- and Na(+)/K(+)-ATPases. Hence, the P4-ATPase mechanism is quite similar to the mechanism of these ion pumps, where the glutamate translocates the ions by moving like a pump rod. The accessory subunit CDC50 may be located in close association with the exoplasmic entrance of the suggested pathway, and possibly promotes the binding of the lipid substrate. This review focuses on properties of mammalian and yeast P4-ATPases for which most mechanistic insight is available. However, the structure, function and enigmas associated with mammalian and yeast P4-ATPases most likely extend to P4-ATPases of plants and other organisms.

Dataset Information

Nematode phospholipid metabolism: an example of closing the genome-structure-function circle.

Publications

Nematode phospholipid metabolism: an example of closing the genome-structure-function circle.

Similar Datasets

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