α-Synuclein and ALPS motifs are membrane curvature sensors whose contrasting chemistry mediates selective vesicle binding

Pranke, Iwona; Morello, Vincent; Bigay, Joëlle; Gibson, Kimberley; Verbavatz, Jean‐Marc; Antonny, Bruno; Jackson, Catherine

doi:10.1083/jcb.201011118

Cited by 184 publications

(222 citation statements)

References 67 publications

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“…Other membrane-binding proteins as well as amphiphilic compounds used in chemical biology might prefer deeper or shallower defects, depending on the amino acid composition of their hydrophobic moiety 35,44,47,48 . These variations, which are also critical in membrane curvature generation mechanisms 49 , are ignored in models where membrane curvature is assumed to simply increase the number of 'binding sites' for peripheral proteins, regardless of the type of hydrophobic moieties 16,17 .…”

Section: Discussionmentioning

confidence: 99%

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

et al. 2014

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Two parameters of biological membranes, curvature and lipid composition, direct the recruitment of many peripheral proteins to cellular organelles. Although these traits are often studied independently, it is their combination that generates the unique interfacial properties of cellular membranes. Here, we use a combination of in vivo, in vitro and in silico approaches to provide a comprehensive map of how these parameters modulate membrane adhesive properties. The correlation between the membrane partitioning of model amphipathic helices and the distribution of lipid-packing defects in membranes of different shape and composition explains how macroscopic membrane properties modulate protein recruitment by changing the molecular topography of the membrane interfacial region. Furthermore, our results suggest that the range of conditions that can be obtained in a cellular context is remarkably large because lipid composition and curvature have, under most circumstances, cumulative effects.

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Section: Discussionmentioning

confidence: 99%

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

et al. 2014

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“…In both yeast and neurons, α-syn associates with lipid rafts, suggesting that α-syn displays similar lipid-binding preferences in both cell types. The exact composition of α-syn's preferred lipid environment is not understood; however, current work suggests that α-syn is sensitive both to the type of lipids and how they are packed into the bilayer (12,13).…”

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confidence: 99%

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Valastyan¹,

Termine²,

Lindquist³

2014

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a number of phenotypes, including blocking vesicle trafficking. The expression of α-syn splice isoforms varies with disease, but how these isoforms affect protein function is unknown. We investigated two of the most abundant isoforms, resulting in deletion of exon four (α-synΔ4) or exon six (α-synΔ6). α-SynΔ4, missing part of the lipid-binding domain, had reduced toxicity and membrane binding. α-SynΔ6, missing part of the protein-protein interaction domain, had reduced toxicity but no reduction in membrane binding. To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn-induced toxicity. Most modifiers equally altered the toxicity induced by the splice isoforms and full-length α-syn (α-synFL). However, the splice isoform strains responded differently to a sterol-binding protein, leading us to examine the effect of sterols on α-syn-induced toxicity. Upon inhibition of sterol synthesis, α-synFL and α-synΔ6, but not α-synΔ4, showed decreased plasma membrane association, increased vesicular association, and increased cellular toxicity. Thus, higher membrane sterol concentrations favor plasma membrane binding of α-synFL and α-synΔ6 and may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and these potential effects on membrane binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted.

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“…Fluorescence F (emission, 535 nm) was measured at 37°C (excitation, 485 nm). Liposomes for binding experiments with ␣-synuclein-NBD contained either PC(18:1/18:1) with PS(18:1/18:1) or PC(16:0/ 18:1) with PS(16:0/18:1) always in a 1:1 molar ratio in the presence of 50 mol % cholesterol and 10 mol % egg PC (30). Incubation, readout, and analysis were the same as for ALPS-NBD except that PUVA treatment was with 150 M amotosalen, and the peptide concentration was 0.25 M. Both NBD-labeled peptides were not exposed to UVA light because binding experiments were performed after PUVA.…”

Section: Effects Of Psoralen and Uva Light On Signal Transductionmentioning

confidence: 99%

“…Binding experiments of the peptidic lipid-packing sensors ␣-synuclein and ALPS were based on the work by Vanni et al (29) and Pranke et al (30). First, the peptides were covalently labeled with NBD to their N termini.…”

Section: Effects Of Psoralen and Uva Light On Signal Transductionmentioning

confidence: 99%

“…Because disordered lipid microenvironments are important for protein-membrane interaction (27,28), two archetypical membrane-adhering protein sequences, ALPS and ␣-synuclein (29,30), were investigated for binding to PUVA-treated liposomes. As expected, the ALPS peptide efficiently bound to increasing concentrations of dark-treated control liposomes enriched in PC(18:1/18:1) but not PC(16:0/18:1) (Fig.…”

Section: Puva Modifies Phospholipids By Covalent Adductmentioning

confidence: 99%

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Psoralen and Ultraviolet A Light Treatment Directly Affects Phosphatidylinositol 3-Kinase Signal Transduction by Altering Plasma Membrane Packing

Aelst¹,

Devloo²,

Zachée

et al. 2016

Journal of Biological Chemistry

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Edited by George CarmanPsoralen and ultraviolet A light (PUVA) are used to kill pathogens in blood products and as a treatment of aberrant cell proliferation in dermatitis, cutaneous T-cell lymphoma, and graftversus-host disease. DNA damage is well described, but the direct effects of PUVA on cell signal transduction are poorly understood. Because platelets are anucleate and contain archetypal signal transduction machinery, they are ideally suited to address this. Lipidomics on platelet membrane extracts showed that psoralen forms adducts with unsaturated carbon bonds of fatty acyls in all major phospholipid classes after PUVA.

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α-Synuclein and ALPS motifs are membrane curvature sensors whose contrasting chemistry mediates selective vesicle binding

Abstract: Two membrane curvature–sensing molecules with opposite chemistries are targeted to distinct vesicle classes through direct interaction with different lipid environments.

Cited by 184 publications

References 67 publications

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Psoralen and Ultraviolet A Light Treatment Directly Affects Phosphatidylinositol 3-Kinase Signal Transduction by Altering Plasma Membrane Packing

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