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Mechanism and Determinants of Amphipathic Helix-Containing Protein Targeting to Lipid Droplets.

ABSTRACT: Cytosolic lipid droplets (LDs) are the main storage organelles for metabolic energy in most cells. They are unusual organelles that are bounded by a phospholipid monolayer and specific surface proteins, including key enzymes of lipid and energy metabolism. Proteins targeting LDs from the cytoplasm often contain amphipathic helices, but how they bind to LDs is not well understood. Combining computer simulations with experimental studies in vitro and in cells, we uncover a general mechanism for targeting of cytosolic proteins to LDs: large hydrophobic residues of amphipathic helices detect and bind to large, persistent membrane packing defects that are unique to the LD surface. Surprisingly, amphipathic helices with large hydrophobic residues from many different proteins are capable of binding to LDs. This suggests that LD protein composition is additionally determined by mechanisms that selectively prevent proteins from binding LDs, such as macromolecular crowding at the LD surface.

SUBMITTER: Prevost C

PROVIDER: S-EPMC5764114 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Mechanism and Determinants of Amphipathic Helix-Containing Protein Targeting to Lipid Droplets.

Prévost Coline C Sharp Morris E ME Kory Nora N Lin Qingqing Q Voth Gregory A GA Farese Robert V RV Walther Tobias C TC

Developmental cell 20180108 1

Cytosolic lipid droplets (LDs) are the main storage organelles for metabolic energy in most cells. They are unusual organelles that are bounded by a phospholipid monolayer and specific surface proteins, including key enzymes of lipid and energy metabolism. Proteins targeting LDs from the cytoplasm often contain amphipathic helices, but how they bind to LDs is not well understood. Combining computer simulations with experimental studies in vitro and in cells, we uncover a general mechanism for ta ...[more]

PMID: 29316443

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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

Mechanism and Determinants of Amphipathic Helix-Containing Protein Targeting to Lipid Droplets.

Publications

Mechanism and Determinants of Amphipathic Helix-Containing Protein Targeting to Lipid Droplets.

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