Role of endosomal membrane lipids and NPC2 in cholesterol transfer and membrane fusion

Synaptotagmin-1 (syt-1) is known to trigger fusion of neuronal synaptic vesicles with the presynaptic membrane by recognizing acidic membrane lipids. In particular, binding to PI(4,5)P2 is believed to be crucial for its function as a calcium sensor. We propose a mechanism for syt-1 to interact with anionic bilayers and promote fusion in the presence of SNARE proteins. We found that in the absence of Ca2+ the binding of syt-1 to membranes depends on the PI(4,5)P2 content. Addition of Ca2+ switches the interaction forces from weak to strong eventually exceeding the cohesion of the C2A domain, while the interaction between PI(4,5)P2 and the C2B domain was preserved even in the absence of Ca2+ or phosphatidylserine. Fusion of large unilamellar vesicles equipped with syt-1 and synaptobrevin with freestanding target membranes composed of PS/PI(4,5)P2 show an increased fusion speed, and by effective suppression of stalled intermediate states, a larger number of full fusion events. Fusion efficiency could be maximized when irreversible docking is additionally prevented by addition of multivalent anions. The picture that emerges is that syt-1 remodels the membrane in the presence of calcium and PIP2, thereby substantially increasing the efficiency of membrane fusion by avoiding stalled intermediate states.

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The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

Current Alzheimer Research ◽

10.2174/1567205015666180911151716 ◽

2018 ◽

Vol 15 (13) ◽

pp. 1191-1212 ◽

Cited By ~ 23

Author(s):

Botond Penke ◽

Gábor Paragi ◽

János Gera ◽

Róbert Berkecz ◽

Zsolt Kovács ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signaling Pathways ◽

Membrane Lipids ◽

Specific Protein ◽

Dietary Factors ◽

Lipid Signaling ◽

Special Role ◽

Aβ Peptides

Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism in AD and provides insight in the current understanding of biological membranes, their lipid structures and functions, as well as their role as potential therapeutic targets. Novel methods for studying the membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the cell membrane and different subcellular organelles are reviewed. Next, the details of the most important lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.

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How do mechanosensitive channels sense membrane tension?

Biochemical Society Transactions ◽

10.1042/bst20160018 ◽

2016 ◽

Vol 44 (4) ◽

pp. 1019-1025 ◽

Cited By ~ 14

Author(s):

Tim Rasmussen

Keyword(s):

Membrane Lipids ◽

Osmotic Shock ◽

Md Simulations ◽

Fatty Acyl ◽

Membrane Bilayer ◽

Cross Sectional ◽

Conducting Path ◽

Lipid Chain ◽

Acyl Chains

Mechanosensitive (MS) channels provide protection against hypo-osmotic shock in bacteria whereas eukaryotic MS channels fulfil a multitude of important functions beside osmoregulation. Interactions with the membrane lipids are responsible for the sensing of mechanical force for most known MS channels. It emerged recently that not only prokaryotic, but also eukaryotic, MS channels are able to directly sense the tension in the membrane bilayer without any additional cofactor. If the membrane is solely viewed as a continuous medium with specific anisotropic physical properties, the sensitivity towards tension changes can be explained as result of the hydrophobic coupling between membrane and transmembrane (TM) regions of the channel. The increased cross-sectional area of the MS channel in the active conformation and elastic deformations of the membrane close to the channel have been described as important factors. However, recent studies suggest that molecular interactions of lipids with the channels could play an important role in mechanosensation. Pockets in between TM helices were identified in the MS channel of small conductance (MscS) and YnaI that are filled with lipids. Less lipids are present in the open state of MscS than the closed according to MD simulations. Thus it was suggested that exclusion of lipid fatty acyl chains from these pockets, as a consequence of increased tension, would trigger gating. Similarly, in the eukaryotic MS channel TRAAK it was found that a lipid chain blocks the conducting path in the closed state. The role of these specific lipid interactions in mechanosensation are highlighted in this review.

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The role of cholesterol in membrane fusion

Chemistry and Physics of Lipids ◽

10.1016/j.chemphyslip.2016.05.003 ◽

2016 ◽

Vol 199 ◽

pp. 136-143 ◽

Cited By ~ 105

Author(s):

Sung-Tae Yang ◽

Alex J.B. Kreutzberger ◽

Jinwoo Lee ◽

Volker Kiessling ◽

Lukas K. Tamm

Keyword(s):

Membrane Fusion

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Sec1p directly stimulates SNARE-mediated membrane fusion in vitro

The Journal of Cell Biology ◽

10.1083/jcb.200405018 ◽

2004 ◽

Vol 167 (1) ◽

pp. 75-85 ◽

Cited By ~ 79

Author(s):

Brenton L. Scott ◽

Jeffrey S. Van Komen ◽

Hassan Irshad ◽

Song Liu ◽

Kirilee A. Wilson ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Membrane Fusion ◽

Membrane Trafficking ◽

Snare Complex ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Bud Neck ◽

Precise Role

Sec1 proteins are critical players in membrane trafficking, yet their precise role remains unknown. We have examined the role of Sec1p in the regulation of post-Golgi secretion in Saccharomyces cerevisiae. Indirect immunofluorescence shows that endogenous Sec1p is found primarily at the bud neck in newly budded cells and in patches broadly distributed within the plasma membrane in unbudded cells. Recombinant Sec1p binds strongly to the t-SNARE complex (Sso1p/Sec9c) as well as to the fully assembled ternary SNARE complex (Sso1p/Sec9c;Snc2p), but also binds weakly to free Sso1p. We used recombinant Sec1p to test Sec1p function using a well-characterized SNARE-mediated membrane fusion assay. The addition of Sec1p to a traditional in vitro fusion assay moderately stimulates fusion; however, when Sec1p is allowed to bind to SNAREs before reconstitution, significantly more Sec1p binding is detected and fusion is stimulated in a concentration-dependent manner. These data strongly argue that Sec1p directly stimulates SNARE-mediated membrane fusion.

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The Role of Histidine Residues in Low-pH-Mediated Viral Membrane Fusion

Structure ◽

10.1016/j.str.2006.07.011 ◽

2006 ◽

Vol 14 (10) ◽

pp. 1481-1487 ◽

Cited By ~ 106

Author(s):

Thorsten Kampmann ◽

Daniela S. Mueller ◽

Alan E. Mark ◽

Paul R. Young ◽

Bostjan Kobe

Keyword(s):

Membrane Fusion ◽

Low Ph ◽

Viral Membrane ◽

Histidine Residues ◽

Viral Membrane Fusion

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Cholesterol provides nonsacrificial protection of membrane lipids from chemical damage at air–water interface

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1722323115 ◽

2018 ◽

Vol 115 (13) ◽

pp. 3255-3260 ◽

Cited By ~ 24

Author(s):

Xinxing Zhang ◽

Kevin M. Barraza ◽

J. L. Beauchamp

Keyword(s):

Lipid Membranes ◽

Membrane Lipids ◽

Oh Radicals ◽

Significant Finding ◽

Water Interface ◽

Unsaturated Lipids ◽

Air Water Interface ◽

Liquid Ordered ◽

Ester Linkage

The role of cholesterol in bilayer and monolayer lipid membranes has been of great interest. On the biophysical front, cholesterol significantly increases the order of the lipid packing, lowers the membrane permeability, and maintains membrane fluidity by forming liquid-ordered–phase lipid rafts. However, direct observation of any influence on membrane chemistry related to these cholesterol-induced physical properties has been absent. Here we report that the addition of 30 mol % cholesterol to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (POPG) monolayers at the air–water interface greatly reduces the oxidation and ester linkage cleavage chemistries initiated by potent chemicals such as OH radicals and HCl vapor, respectively. These results shed light on the indispensable chemoprotective function of cholesterol in lipid membranes. Another significant finding is that OH oxidation of unsaturated lipids generates Criegee intermediate, which is an important radical involved in many atmospheric processes.

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