Synergistic actions of v-SNARE transmembrane domains and membrane-curvature modifying lipids in neurotransmitter release

Dhara, Madhurima; Martinez, Maria Mantero; Makke, Mazen; Schwarz, Yvonne; Mohrmann, Ralf; Bruns, Dieter

doi:10.7554/elife.55152

Cited by 21 publications

(15 citation statements)

References 59 publications

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“…In the context of membrane fusion, PMFs could rationalize the role of the lipid composition and of transmembrane helices during fusion pore opening and expansion. 66 In addition, we anticipate that the RC may be used to study stalk formation and stalk widening, during which the hydrophobic membrane cores carry out similar topological transition as the water phase during pore formation and expansion. 3,67 zero if R(r) = 0.…”

Section: Discussionmentioning

confidence: 99%

A joint reaction coordinate for computing the free energy landscape of pore nucleation and pore expansion in lipid membranes

Hub

2020

Preprint

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Topological transitions of membranes, such as pore formation or membrane fusion, play key roles in biology, biotechnology, and in medical applications. Calculating the related free energy landscapes has been complicated by the fact that such processes involve a sequence of transitions along highly distinct directions in conformational space, making it difficult to define good reaction coordinates (RCs) for the overall process. In this study, we present a new RC capable of driving both pore nucleation and pore expansion in lipid membranes. The potential of mean force (PMF) along the RC computed with molecular dynamics (MD) simulations provides a comprehensive view on the free-energy landscape of pore formation, including a barrier for pore nucleation, the size, free energy, and metastability of the open pore, and the energetic cost for further pore expansion against the line tension of the pore rim. We illustrate the RC by quantifying the effects (i) of simulation system size and (ii) of the addition of dimethyl sulfoxide (DMSO) on the free energy landscape of pore formation. PMF calculations along the RC provide mechanistic and energetic understanding of pore formation, hence they will be useful to rationalize the effects of membrane-active peptides, electric fields, and membrane composition on transmembrane pores.Graphical TOC Entry

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Section: Discussionmentioning

confidence: 99%

A joint reaction coordinate for computing the free energy landscape of pore nucleation and pore expansion in lipid membranes

Hub

2020

Preprint

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“…In line with this, the administration of LPC and oleic acid to the cell culture medium, which increases their concentrations in the outer leaflet of the plasma membrane, accelerated and deaccelerated nurotransmitter release, respectively ( Dhara et al, 2020 ). In contrast, the intracellular administration of LPC and oleic acid by microinjection, which increased their concentration in the inner leaflet of the plasma membrane, blocked and promoted membrane fusion, respectively ( Dhara et al, 2020 ). Similar results were also obtained in homotypic fusion of cortical vesicles isolated from eggs of the sea urchin, in which increasing the LPC concentrations in the outer leaflets of these vesicles by external LPC blocked fusion ( Dabral and Coorssen, 2019 ).…”

Section: Discussion and Concluding Remarksmentioning

confidence: 92%

“…Cognate SNARE proteins in both the vesicular and target membranes, called v- and t-SNAREs, engage and “zipper” from their N-terminal toward their C-terminal termini, thereby forming a tight alpha-helical coiled-coil bundle that overcomes the energy barrier of membrane fusion ( Dingjan et al, 2018 ). In mouse chromaffin cells, the transmembrane domain of the v-SNAREs VAMP2 is affected by the PLA 2 metabolites LPC and oleic acid in a leaflet specific manner that either promotes or inhibits fusion pore formation and expansion, hence affecting neurotransmitter release ( Dhara et al, 2020 ). In line with this, the administration of LPC and oleic acid to the cell culture medium, which increases their concentrations in the outer leaflet of the plasma membrane, accelerated and deaccelerated nurotransmitter release, respectively ( Dhara et al, 2020 ).…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

“…In mouse chromaffin cells, the transmembrane domain of the v-SNAREs VAMP2 is affected by the PLA 2 metabolites LPC and oleic acid in a leaflet specific manner that either promotes or inhibits fusion pore formation and expansion, hence affecting neurotransmitter release ( Dhara et al, 2020 ). In line with this, the administration of LPC and oleic acid to the cell culture medium, which increases their concentrations in the outer leaflet of the plasma membrane, accelerated and deaccelerated nurotransmitter release, respectively ( Dhara et al, 2020 ). In contrast, the intracellular administration of LPC and oleic acid by microinjection, which increased their concentration in the inner leaflet of the plasma membrane, blocked and promoted membrane fusion, respectively ( Dhara et al, 2020 ).…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

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The Roles of Phospholipase A2 in Phagocytes

Dabral

Bogaart

2021

Front. Cell Dev. Biol.

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Phagocytic cells, such as macrophages, neutrophils, and dendritic cells, ingest particles larger than about 0.5 μM and thereby clear microbial pathogens and malignant cells from the body. These phagocytic cargoes are proteolytically degraded within the lumen of phagosomes, and peptides derived from them are presented on Major Histocompatibility Complexes (MHC) for the activation of T cells. Mammalian PLA2 isozymes belong to a large family of enzymes that cleave phospholipids at the second position of the glycerol backbone, releasing a free fatty acid and a lysolipid moiety. In human macrophages, at least 15 different PLA2 forms are expressed, and expression of many of these is dependent on pathogenic stimulation. Intriguing questions are why so many PLA2 forms are expressed in macrophages, and what are the functional consequences of their altered gene expression after encountering pathogenic stimuli. In this review, we discuss the evidence of the differential roles of different forms of PLA2 in phagocytic immune cells. These roles include: lipid signaling for immune cell activation, initial phagocytic particle uptake, microbial action for the killing and degradation of ingested microbes, and the repair of membranes induced by oxygen radicals. We also discuss the roles of PLA2 in the subsequent digestion of ingested phagocytic cargoes for antigen presentation to T cells.

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“…Stalk widening as well as opening and expansion of the fusion pore involve highly curved membranes and are therefore controlled by lipid curvature. 10,39 Hence, future studies should quantify the role of complex lipid compositions on such later stages of fusion, in addition to lipid effects on the dehydration repulsion, which may add a free energy offset to the free energies of stalk formation computed here. 27 Further, it will be interesting to test whether lipid-protein interactions guide a local enrichment of fusogenic lipids and, thereby, further facilitate fusion.…”

Section: Discussionmentioning

confidence: 98%

Free energies of stalk formation in the lipidomics era

Poojari

Scherer

Hub

2021

Preprint

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Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at near-atomic resolution. The new method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes.

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Synergistic actions of v-SNARE transmembrane domains and membrane-curvature modifying lipids in neurotransmitter release

Cited by 21 publications

References 59 publications

A joint reaction coordinate for computing the free energy landscape of pore nucleation and pore expansion in lipid membranes

A joint reaction coordinate for computing the free energy landscape of pore nucleation and pore expansion in lipid membranes

The Roles of Phospholipase A2 in Phagocytes

Free energies of stalk formation in the lipidomics era

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