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A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase.

ABSTRACT: Regulation of membrane lipid composition is crucial for many aspects of cell growth and development. Lipins, a novel family of phosphatidate (PA) phosphatases that generate diacylglycerol (DAG) from PA, are emerging as essential regulators of fat metabolism, adipogenesis, and organelle biogenesis. The mechanisms that govern lipin translocation onto membranes are largely unknown. Here we show that recruitment of the yeast lipin (Pah1p) is regulated by PA levels onto the nuclear/endoplasmic reticulum (ER) membrane. Recruitment requires the transmembrane protein phosphatase complex Nem1p-Spo7p. Once dephosphorylated, Pah1p can bind to the nuclear/ER membrane independently of Nem1p-Spo7p via a short amino-terminal amphipathic helix. Dephosphorylation enhances the activity of Pah1p, both in vitro and in vivo, but only in the presence of a functional helix. The helix is required for both phospholipid and triacylglycerol biosynthesis. Our data suggest that dephosphorylation of Pah1p by the Nem1p-Spo7p complex enables the amphipathic helix to anchor Pah1p onto the nuclear/ER membrane allowing the production of DAG for lipid biosynthesis.

SUBMITTER: Karanasios E

PROVIDER: S-EPMC2955120 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase.

Karanasios Eleftherios E Han Gil-Soo GS Xu Zhi Z Carman George M GM Siniossoglou Symeon S

Proceedings of the National Academy of Sciences of the United States of America 20100927 41

Regulation of membrane lipid composition is crucial for many aspects of cell growth and development. Lipins, a novel family of phosphatidate (PA) phosphatases that generate diacylglycerol (DAG) from PA, are emerging as essential regulators of fat metabolism, adipogenesis, and organelle biogenesis. The mechanisms that govern lipin translocation onto membranes are largely unknown. Here we show that recruitment of the yeast lipin (Pah1p) is regulated by PA levels onto the nuclear/endoplasmic reticu ...[more]

PMID: 20876142

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Project description:One of the fundamental features of biomembranes is the ability to fuse or to separate. These processes called respectively membrane fusion and fission are central in the homeostasis of events such as those related to intracellular membrane traffic. Proteins that contain amphipathic helices (AHs) were suggested to mediate membrane fission via shallow insertion of these helices into the lipid bilayer. Here we analyze the AH-containing proteins that have been identified as essential for membrane fission and categorize them in few subfamilies, including small GTPases, Atg proteins, and proteins containing either the ENTH/ANTH- or the BAR-domain. AH-containing fission-inducing proteins may require cofactors such as additional proteins (e.g., lipid-modifying enzymes), or lipids (e.g., phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], phosphatidic acid [PA], or cardiolipin). Both PA and cardiolipin possess a cone shape and a negative charge (-2) that favor the recruitment of the AHs of fission-inducing proteins. Instead, PtdIns(4,5)P2 is characterized by an high negative charge able to recruit basic residues of the AHs of fission-inducing proteins. Here we propose that the AHs of fission-inducing proteins contain sequence motifs that bind lipid cofactors; accordingly (K/R/H)(K/R/H)xx(K/R/H) is a PtdIns(4,5)P2-binding motif, (K/R)x6(F/Y) is a cardiolipin-binding motif, whereas KxK is a PA-binding motif. Following our analysis, we show that the AHs of many fission-inducing proteins possess five properties: (a) at least three basic residues on the hydrophilic side, (b) ability to oligomerize, (c) optimal (shallow) depth of insertion into the membrane, (d) positive cooperativity in membrane curvature generation, and (e) specific interaction with one of the lipids mentioned above. These lipid cofactors favor correct conformation, oligomeric state and optimal insertion depth. The most abundant lipid in a given organelle possessing high negative charge (more negative than -1) is usually the lipid cofactor in the fission event. Interestingly, naturally occurring mutations have been reported in AH-containing fission-inducing proteins and related to diseases such as centronuclear myopathy (amphiphysin 2), Charcot-Marie-Tooth disease (GDAP1), Parkinson's disease (?-synuclein). These findings add to the interest of the membrane fission process whose complete understanding will be instrumental for the elucidation of the pathogenesis of diseases involving mutations in the protein AHs.

Dataset Information

A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase.

Publications

A phosphorylation-regulated amphipathic helix controls the membrane translocation and function of the yeast phosphatidate phosphatase.

Similar Datasets

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