Membrane Curvature Sensing by Amphipathic Helices

Jensen, Martin Borch; Bhatia, Vikram; Jao, Christine C.; Rasmussen, Jacob; Pedersen, Sven; Jensen, Knud J.; Langen, Ralf; Stamou, Dimitrios

doi:10.1074/jbc.m111.271130

Cited by 110 publications

(62 citation statements)

References 65 publications

(103 reference statements)

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“…The association of α-synuclein with lipid bilayers induces membrane curvature, tubulation, and disruption [7], [8]. These observations are remarkably similar to our previous studies of adenovirus protein VI.…”

Section: Introductionsupporting

confidence: 90%

Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis

et al. 2013

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α-synuclein dysregulation is a critical aspect of Parkinson's disease pathology. Recent studies have observed that α-synuclein aggregates are cytotoxic to cells in culture and that this toxicity can be spread between cells. However, the molecular mechanisms governing this cytotoxicity and spread are poorly characterized. Recent studies of viruses and bacteria, which achieve their cytoplasmic entry by rupturing intracellular vesicles, have utilized the redistribution of galectin proteins as a tool to measure vesicle rupture by these organisms. Using this approach, we demonstrate that α-synuclein aggregates can induce the rupture of lysosomes following their endocytosis in neuronal cell lines. This rupture can be induced by the addition of α-synuclein aggregates directly into cells as well as by cell-to-cell transfer of α-synuclein. We also observe that lysosomal rupture by α-synuclein induces a cathepsin B dependent increase in reactive oxygen species (ROS) in target cells. Finally, we observe that α-synuclein aggregates can induce inflammasome activation in THP-1 cells. Lysosomal rupture is known to induce mitochondrial dysfunction and inflammation, both of which are well established aspects of Parkinson's disease, thus connecting these aspects of Parkinson's disease to the propagation of α-synuclein pathology in cells.

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Section: Introductionsupporting

confidence: 90%

Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis

et al. 2013

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“…Acidic headgroups are found on the cytoplasmic leaflet of many intracellular membranes, but synuclein has a preference for membranes with high curvature (Jensen et al, 2011; Middleton and Rhoades, 2010), and synaptic vesicles are among the smallest biological membranes described. Consistent with this, synuclein disperses from presynaptic boutons with stimulation (Fortin et al, 2005), suggesting that it dissociates from the membrane upon delivery to the relatively flat plasma membrane by synaptic vesicle exocytosis.…”

Section: Membrane Interactions and The Presynaptic Location Of Synucleinmentioning

confidence: 99%

“…4B). However, synuclein seems to act through a distinct mechanism that may involve electrostatic interaction with the phospholipid headgroups to bind membranes but requires insertion into the bilayer for membrane bending (Jensen et al, 2011). In particular, synuclein appears to insert in an extended helical conformation parallel to the long axis of the tubule (Mizuno et al, 2012).…”

Section: Toxicity: Membranesmentioning

confidence: 99%

The Function of α-Synuclein

Bendor

Logan

Edwards

2013

Neuron

685

613

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Human genetics has indicated a causal role for the protein α-synuclein in the pathogenesis of familial Parkinson’s disease (PD), and the aggregation of synuclein in essentially all patients with PD suggests a central role for this protein in the sporadic disorder. Indeed, the accumulation of misfolded α-synuclein now defines multiple forms of neural degeneration. Like many of the proteins that accumulate in other neurodegenerative disorders, however, the normal function of synuclein remains poorly understood. α-Synuclein localizes specifically to the nerve terminal and inhibits neurotransmitter release when over-expressed, but the knockout has a modest effect on synaptic transmission, suggesting alternative presynaptic roles. Natively unstructured, synuclein adopts a helical conformation on membrane binding and recent work suggests a role in membrane remodeling. In neural degeneration, synuclein misfolds and aggregates as a β-sheet. Multiple observations now suggest propagation of the misfolded protein as a prion, providing a mechanism for the spread of degeneration through the neuraxis. However, the factors that trigger the original misfolding remain unknown.

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“…13,14 Amphipathic membrane-surface helices have been shown to promote curvature in several systems, 15–17 presumably due to their ability to cause lipid-packing defects that induce curvature. As a homotetramer, the M2 protein contains four amphipathic helices, but it is not understood how the four helices are arranged with respect to each other and how they work in concert to promote viral budding.…”

mentioning

confidence: 99%

Cholesterol-Dependent Conformational Exchange of the C-Terminal Domain of the Influenza A M2 Protein

et al. 2015

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The C-terminal amphipathic helix of the influenza A M2 protein plays a critical cholesterol dependent role in viral budding. To provide atomic-level detail on the impact cholesterol has on the conformation of M2 protein, we spin-labeled sites right before and within the C-terminal amphipathic helix of the M2 protein. We studied the spin-labeled M2 proteins in membranes both with and without cholesterol. We used a multipronged site-directed spin-label electron paramagnetic resonance (SDSL-EPR) approach and collected data on line shapes, relaxation rates, accessibility of sites to the membrane, and distances between symmetry related sites within the tetrameric protein. We demonstrate that the C-terminal amphipathic helix of M2 populates at least two conformations in POPC/POPG 4:1 bilayers. Furthermore, we show that the conformational state that becomes more populated in the presence of cholesterol is less dynamic, less membrane buried, and more tightly packed than the other state. Cholesterol dependent changes in M2 could be attributed to the changes cholesterol induces in bilayer properties and/or direct binding of cholesterol to the protein. We propose a model consistent with all our experimental data that suggests that the predominant conformation we observe in the presence of cholesterol is relevant for the understanding of viral budding.

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Membrane Curvature Sensing by Amphipathic Helices

Cited by 110 publications

References 65 publications

Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis

Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis

The Function of α-Synuclein

Cholesterol-Dependent Conformational Exchange of the C-Terminal Domain of the Influenza A M2 Protein

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