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Structure and mechanism of an intramembrane liponucleotide synthetase central for phospholipid biosynthesis.

ABSTRACT: Phospholipids are elemental building-block molecules for biological membranes. Biosynthesis of phosphatidylinositol, phosphatidylglycerol and phosphatidylserine requires a central liponucleotide intermediate named cytidine-diphosphate diacylglycerol (CDP-DAG). The CDP-DAG synthetase (Cds) is an integral membrane enzyme catalysing the formation of CDP-DAG, an essential step for phosphoinositide recycling during signal transduction. Here we report the structure of the Cds from Thermotoga maritima (TmCdsA) at 3.4 Å resolution. TmCdsA forms a homodimer and each monomer contains nine transmembrane helices arranged into a novel fold with three domains. An unusual funnel-shaped cavity penetrates half way into the membrane, allowing the enzyme to simultaneously accept hydrophilic substrate (cytidine 5'-triphosphate (CTP)/deoxy-CTP) from cytoplasm and hydrophobic substrate (phosphatidic acid) from membrane. Located at the bottom of the cavity, a Mg(2+)-K(+) hetero-di-metal centre coordinated by an Asp-Asp dyad serves as the cofactor of TmCdsA. The results suggest a two-metal-ion catalytic mechanism for the Cds-mediated synthesis of CDP-DAG at the membrane-cytoplasm interface.

SUBMITTER: Liu X

PROVIDER: S-EPMC4083444 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Structure and mechanism of an intramembrane liponucleotide synthetase central for phospholipid biosynthesis.

Liu Xiuying X Yin Yan Y Wu Jinjun J Liu Zhenfeng Z

Nature communications 20140627

Phospholipids are elemental building-block molecules for biological membranes. Biosynthesis of phosphatidylinositol, phosphatidylglycerol and phosphatidylserine requires a central liponucleotide intermediate named cytidine-diphosphate diacylglycerol (CDP-DAG). The CDP-DAG synthetase (Cds) is an integral membrane enzyme catalysing the formation of CDP-DAG, an essential step for phosphoinositide recycling during signal transduction. Here we report the structure of the Cds from Thermotoga maritima ...[more]

PMID: 24968740

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Project description:BackgroundAlcadein proteins (Alcs; Alc?, Alc?and Alc?) are predominantly expressed in neurons, as is Alzheimer's ?-amyloid (A?) precursor protein (APP). Both Alcs and APP are cleaved by primary ?- or ?-secretase to generate membrane-associated C-terminal fragments (CTFs). Alc CTFs are further cleaved by ?-secretase to secrete p3-Alc peptide along with the release of intracellular domain fragment (Alc ICD) from the membrane. In the case of APP, APP CTF? is initially cleaved at the ?-site to release the intracellular domain fragment (AICD) and consequently the ?-site is determined, by which A? generates. The initial ?-site is thought to define the final ?-site position, which determines whether A?40/43 or A?42 is generated. However, initial intracellular ?-cleavage sites of Alc CTF to generate Alc ICD and the molecular mechanism that final ?-site position is determined remains unclear in Alcs.MethodologyUsing HEK293 cells expressing Alcs plus presenilin 1 (PS1, a catalytic unit of ?-secretase) and the membrane fractions of these cells, the generation of p3-Alc possessing C-terminal ?-cleavage site and Alc ICD possessing N-terminal ?-cleavage site were analysed with MALDI-TOF/MS. We determined the initial ?-site position of all Alc?, Alc? and Alc?, and analyzed the relationship between the initially determined ?-site position and the final ?-cleavage position.ConclusionsThe initial ?-site position does not always determine the final ?-cleavage position in Alcs, which differed from APP. No additional ?-cleavage sites are generated from artificial/non-physiological positions of ?-cleavage for Alcs, while the artificial ?-cleavage positions can influence in selection of physiological ?-site positions. Because alteration of ?-secretase activity is thought to be a pathogenesis of sporadic Alzheimer's disease, Alcs are useful and sensitive substrate to detect the altered cleavage of substrates by ?-secretase, which may be induced by malfunction of ?-secretase itself or changes of membrane environment for enzymatic reaction.

Dataset Information

Structure and mechanism of an intramembrane liponucleotide synthetase central for phospholipid biosynthesis.

Publications

Structure and mechanism of an intramembrane liponucleotide synthetase central for phospholipid biosynthesis.

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