scholarly journals A hemifused complex is the hub in a network of pathways to membrane fusion

2021 ◽  
Author(s):  
Jason Warner ◽  
Dong An ◽  
Benjamin Stratton ◽  
Ben O'Shaughnessy
Keyword(s):  
Membrane Fusion ◽  
Experimental Studies ◽  
Cell Penetrating Peptides ◽  
Vesicle Membrane ◽  
Membrane Rupture ◽  
Dead End ◽  
High Tension ◽  
Delivery Strategies ◽  
Planar Membranes ◽  
Over 40 Years

Membrane fusion is required for essential processes from neurotransmission to fertilization. For over 40 years protein-free fusion driven by calcium or other cationic species has provided a simplified model of biological fusion, but the mechanisms remain poorly understood. Cation-mediated membrane fusion and permeation are essential in their own right to drug delivery strategies based on cell-penetrating peptides or cation-bearing lipid nanoparticles. Experimental studies suggest cations drive anionic membranes to a hemifused intermediate which serves as a hub for a network of pathways, but the pathway selection mechanism is unknown. Here we develop a mathematical model that identifies the network hub as a highly dynamical hemifusion complex. We find multivalent cations drive expansion of a high tension hemifusion interface between interacting vesicles during a brief transient. During this window, rupture of the interface competes with vesicle membrane rupture to determine the outcome, either fusion, dead-end hemifusion or vesicle lysis. The model reproduces the unexplained finding that fusion of vesicles with planar membranes typically stalls at hemifusion, and we show that the equilibrated hemifused state is a novel lens-shaped complex. Thus, membrane fusion kinetics follow a stochastic trajectory within a network of pathways, with outcome weightings set by fusogen concentration, vesicle size, lipid composition and geometry.

Studies of membrane fusion. VI. Mechanism of the membrane fusion and cell swelling stages of Sendai virus-mediated cell fusion

1980 ◽  
Vol 43 (1) ◽  
pp. 103-118
Author(s):  
S. Knutton
Keyword(s):  
Membrane Fusion ◽  
Cell Fusion ◽  
Sendai Virus ◽  
Freeze Fracture ◽  
Viral Envelope ◽  
Cell Swelling ◽  
Fusion Event ◽  
Virus Envelope ◽  
Membrane Rupture ◽  
Membrane Tubules

The membrane fusion and cell swelling stages of Sendai virus-mediated cell-cell fusion have been studied by thin-section and freeze-fracture electron microscopy. Sites of membrane fusion have been detected in human erythrocytes arrested at the membrane fusion stage of cell fusion and in virtually all cases a fused viral envelope or envelope components has been identified thus providing further direct evidence that cell-viral envelope-cell bridge formation is the membrane fusion event in Sendai virus-induced cell fusion. Radial expansion of a single virus bridge connecting 2 cells is sufficient to produce a fused cell. Membrane redistribution which occurs during this cell swelling stage of the fusion process is often accompanied by the formation of a system of membrane tubules in the plane of expansion of the virus bridge. The tubules originate from points of fusion between the bridging virus envelope and the erythrocyte membrane and also expand radially as cells swell. Ultimately membrane rupture occurs and the tubules appear to break down as small vesicles. When previously observed in cross-sectioned cells these membrane tubules were interpreted as sites of direct membrane fusion. The present study indicates that this interpretation is incorrect and shows that the tubules are generated subsequent to membrane fusion when 2 cells connected by a virus bridge are induced to swell. A mechanism to explain the formation of this system of membrane tubules is proposed.

scholarly journals The TIP30 Protein Complex, Arachidonic Acid and Coenzyme A Are Required for Vesicle Membrane Fusion

PLoS ONE ◽  
2011 ◽  
Vol 6 (6) ◽  
pp. e21233 ◽  
Author(s):  
Chengliang Zhang ◽  
Aimin Li ◽  
Shenglan Gao ◽  
Xinchun Zhang ◽  
Hua Xiao
Keyword(s):  
Arachidonic Acid ◽  
Membrane Fusion ◽  
Protein Complex ◽  
Coenzyme A ◽  
Vesicle Membrane

scholarly journals Leaky Intermediates and Possible Dead-End Configurations in Membrane Fusion

2018 ◽  
Vol 114 (3) ◽  
pp. 606a
Author(s):  
Rodion Yu Molotkovskiy ◽  
Timur R. Galimzyanov ◽  
Piotr I. Kuzmin ◽  
Sergey A. Akimov
Keyword(s):  
Membrane Fusion ◽  
Dead End

Disassembly of the reconstituted synaptic vesicle membrane fusion complex in vitro.

1995 ◽  
Vol 14 (10) ◽  
pp. 2317-2325 ◽  
Author(s):  
T. Hayashi ◽  
S. Yamasaki ◽  
S. Nauenburg ◽  
T. Binz ◽  
H. Niemann
Keyword(s):  
Membrane Fusion ◽  
Synaptic Vesicle ◽  
Vesicle Membrane

scholarly journals Hydrostatic pressures developed by osmotically swelling vesicles bound to planar membranes.

1989 ◽  
Vol 93 (2) ◽  
pp. 211-244 ◽  
Author(s):  
W D Niles ◽  
F S Cohen ◽  
A Finkelstein
Keyword(s):  
Contact Region ◽  
Irreversible Thermodynamics ◽  
Open Channels ◽  
Vesicle Membrane ◽  
Osmotic Swelling ◽  
Solute Permeability ◽  
Membrane Permeabilities ◽  
Membrane Contact ◽  
Planar Membrane ◽  
Planar Membranes

When phospholipid vesicles bound to a planar membrane are osmotically swollen, they develop a hydrostatic pressure (delta P) and fuse with the membrane. We have calculated the steady-state delta P, from the equations of irreversible thermodynamics governing water and solute flows, for two general methods of osmotic swelling. In the first method, vesicles are swollen by adding a solute to the vesicle-containing compartment to make it hyperosmotic. delta P is determined by the vesicle membrane's permeabilities to solute and water. If the vesicle membrane is devoid of open channels, then delta P is zero. When the vesicle membrane contains open channels, then delta P peaks at a channel density unique to the solute permeability properties of both the channel and the membrane. The solute enters the vesicle through the channels but leaks out through the region of vesicle-planar membrane contact. delta P is largest for channels having high permeabilities to the solute and for solutes with low membrane permeabilities in the contact region. The model predicts the following order of solutes producing pressures of decreasing magnitude: KCl greater than urea greater than formamide greater than or equal to ethylene glycol. Differences between osmoticants quantitatively depend on the solute permeability of the channel and the density of channels in the vesicle membrane. The order of effectiveness is the same as that experimentally observed for solutes promoting fusion. Therefore, delta P drives fusion. When channels with small permeabilities are used, coupling between solute and water flows within the channel has a significant effect on delta P. In the second method, an impermeant solute bathing the vesicles is isosmotically replaced by a solute which permeates the channels in the vesicle membrane. delta P resulting from this method is much less sensitive to the permeabilities of the channel and membrane to the solute. delta P approaches the theoretical limit set by the concentration of the impermeant solute.

Current Delivery Strategies to Improve the Target of Cell Penetrating Peptides Used for Tumor-Related Therapeutics

2018 ◽  
Vol 24 (5) ◽  
pp. 541-548 ◽  
Author(s):  
Fang Zhang ◽  
Dandan Yang ◽  
Shanshan Jiang ◽  
Lei Wu ◽  
Li Qin ◽  
...  
Keyword(s):  
Tumor Therapy ◽  
Cell Penetrating Peptides ◽  
Theoretical Background ◽  
Laboratory Research ◽  
Transport Efficiency ◽  
Promising Tool ◽  
Wide Range ◽  
Cell Penetrating ◽  
Delivery Strategies ◽  
Gain Access

Cell Penetrating Peptides (CPPs) equipped with a high penetrating ability are used as a promising tool to gain access to the cell interior, cross the cell membrane and deliver bioactive small or macromolecular cargos into the cytoplasm or nucleus. The superiority of wide range of applications, high transport efficiency and low biological toxicity make them particularly desirable in laboratory or clinical studies. Previous studies have shown that their non-selectivity and reaction with proteins in plasma hamper their application for tumor therapy, which might adversely affect the treatment effect and even induce some side effects. However, several recent studies have found that various kinds of modifiers of CPPs can effectively increase the target selectivity, reduce cytotoxicity to normal cells and produce multiple antitumor functions due to the different cleavable bonds which are sensitive to the tumor microenvironment or other novel designs. Apparently, these designs of ‘smart’ CPPs appear to be promising in the field of antitumor drug delivery. Here, we review these current improved approaches which mainly involve strategies of physical, chemical as well as biological pathways and we also explain the possible uptake mechanisms of direct penetration, internalization and escape which have been discussed in some publications with specific attention. In addition, some possible problems needed to be considered in the process of improving CPPs are discussed at the end of this review. This study aims to present an overview of the latest progress of CPPs, and provides a comprehensive theoretical background and reference guidance for future laboratory research and clinical application.

scholarly journals Liposome Model Systems to Study the Endosomal Escape of Cell-Penetrating Peptides: Transport across Phospholipid Membranes Induced by a Proton Gradient

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Fatemeh Madani ◽  
Alex Perálvarez-Marín ◽  
Astrid Gräslund
Keyword(s):  
Cell Penetrating Peptides ◽  
Proton Pumping ◽  
Model Systems ◽  
Endosomal Escape ◽  
Vesicle Membrane ◽  
Large Unilamellar Vesicles ◽  
Octyl Glucoside ◽  
Cell Penetrating ◽  
Pumping Activity ◽  
Extrusion Method

Detergent-mediated reconstitution of bacteriorhodopsin (BR) into large unilamellar vesicles (LUVs) was investigated, and the effects were carefully characterized for every step of the procedure. LUVs were prepared by the extrusion method, and their size and stability were examined by dynamic light scattering. BR was incorporated into the LUVs using the detergent-mediated reconstitution method and octyl glucoside (OG) as detergent. The result of measuring pH outside the LUVs suggested that in the presence of light, BR pumps protons from the outside to the inside of the LUVs, creating acidic pH inside the vesicles. LUVs with 20% negatively charged headgroups were used to model endosomes with BR incorporated into the membrane. The fluorescein-labeled cell-penetrating peptide penetratin was entrapped inside these BR-containing LUVs. The light-induced proton pumping activity of BR has allowed us to observe the translocation of fluorescein-labeled penetratin across the vesicle membrane.

On the mechanism of inhibition of viral and vesicle membrane fusion by carbobenzoxy-D-phenylalanyl-L-phenylalanylglycine

Biochemistry ◽  
1992 ◽  
Vol 31 (12) ◽  
pp. 3177-3183 ◽  
Author(s):  
Philip L. Yeagle ◽  
Joyce Young ◽  
S. W. Hui ◽  
Richard M. Epand
Keyword(s):  
Membrane Fusion ◽  
Vesicle Membrane ◽  
Mechanism Of Inhibition
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