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Membrane Fusion

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 March 2018) | Viewed by 65251

Special Issue Editor

Department of Biochemistry, Iowa State University, Ames, IA, USA
Interests: mechanism of fast synaptic vesicle fusion; spin labeling electron paramagnetic resonance (EPR); single molecule fluorescence
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Membrane fusion is imperative for a wide variety of important biological events such as fertilization, viral infection to host cells, neurotransmitter release, muscle fiber formation, and trafficking in cells. Membrane fusion is a rather simple physics problem in that two separate bilayers merge to form a continuous single bilayer. However, there is wide variation in the sequence and the structure of proteins mediating specific membrane fusion. Extensive structural investigations have now revealed some structural regularities shared by many of these proteins. Moreover, some principles underlying protein conformational changes, necessary to provide the free energy for membrane fusion, have been uncovered. Meanwhile, although it is established that for virus–cell membrane fusion, it transits through hemifusion—a state in which two bilayers are half-fused—there is still controversy as to whether hemifusion is an on-pathway intermediate or not in synaptic vesicle fusion. Furthermore, the functional role that the transmembrane domains of the fusion protein play remain to be fully understood. Yet, the emergence of revolutionary biophysical tools such as single molecule fluorescence and cryo-electron microscopy open up tremendous possibilities of visualizing the major intermediates and characterizing the transitions along the fusion pathway. Importantly, these methods are not limited to the in vitro environments but can be applied directly to the membrane fusion event as it happens in cells. Thus, the time is right to publish a dedicated Special Issue that will include comprehensive reviews, provocative ideas, and insightful new results, which will collectively define the roadmap for the research in membrane fusion. We cordially invite the submission of review or original research papers for the Special Issue.

Prof. Dr. Yeon-Kyun Shin
Guest Editor

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Keywords

  • hemagglutinin
  • HIV gp41
  • SNARE
  • bilayer
  • hemifusion
  • fusion pore
  • membrane remodeling
  • coiled coil

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Published Papers (10 papers)

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Research

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15 pages, 2492 KiB  
Article
Lateral Membrane Heterogeneity Regulates Viral-Induced Membrane Fusion during HIV Entry
by Rodion J. Molotkovsky, Veronika V. Alexandrova, Timur R. Galimzyanov, Irene Jiménez-Munguía, Konstantin V. Pavlov, Oleg V. Batishchev and Sergey A. Akimov
Int. J. Mol. Sci. 2018, 19(5), 1483; https://doi.org/10.3390/ijms19051483 - 16 May 2018
Cited by 22 | Viewed by 5088
Abstract
Sphingomyelin- and cholesterol- enriched membrane domains, commonly referred to as “rafts” play a crucial role in a large number of intra- and intercellular processes. Recent experiments suggest that not only the volumetric inhomogeneity of lipid distribution in rafts, but also the arrangement of [...] Read more.
Sphingomyelin- and cholesterol- enriched membrane domains, commonly referred to as “rafts” play a crucial role in a large number of intra- and intercellular processes. Recent experiments suggest that not only the volumetric inhomogeneity of lipid distribution in rafts, but also the arrangement of the 1D boundary between the raft and the surrounding membrane is important for the membrane-associated processes. The reason is that the boundary preferentially recruits different peptides, such as HIV (human immunodeficiency virus) fusion peptide. In the present work, we report a theoretical investigation of mechanisms of influence of the raft boundary arrangement upon virus-induced membrane fusion. We theoretically predict that the raft boundary can act as an attractor for viral fusion peptides, which preferentially distribute into the vicinity of the boundary, playing the role of ‘line active components’ of the membrane (‘linactants’). We have calculated the height of the fusion energy barrier and demonstrated that, in the case of fusion between HIV membrane and the target cell, presence of the raft boundary in the vicinity of the fusion site facilitates fusion. The results we obtained can be further generalized to be applicable to other enveloped viruses. Full article
(This article belongs to the Special Issue Membrane Fusion)
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15 pages, 2106 KiB  
Article
Phosphatidylcholine Membrane Fusion Is pH-Dependent
by Sergey A. Akimov, Michael A. Polynkin, Irene Jiménez-Munguía, Konstantin V. Pavlov and Oleg V. Batishchev
Int. J. Mol. Sci. 2018, 19(5), 1358; https://doi.org/10.3390/ijms19051358 - 03 May 2018
Cited by 18 | Viewed by 4571
Abstract
Membrane fusion mediates multiple vital processes in cell life. Specialized proteins mediate the fusion process, and a substantial part of their energy is used for topological rearrangement of the membrane lipid matrix. Therefore, the elastic parameters of lipid bilayers are of crucial importance [...] Read more.
Membrane fusion mediates multiple vital processes in cell life. Specialized proteins mediate the fusion process, and a substantial part of their energy is used for topological rearrangement of the membrane lipid matrix. Therefore, the elastic parameters of lipid bilayers are of crucial importance for fusion processes and for determination of the energy barriers that have to be crossed for the process to take place. In the case of fusion of enveloped viruses (e.g., influenza) with endosomal membrane, the interacting membranes are in an acidic environment, which can affect the membrane’s mechanical properties. This factor is often neglected in the analysis of virus-induced membrane fusion. In the present work, we demonstrate that even for membranes composed of zwitterionic lipids, changes of the environmental pH in the physiologically relevant range of 4.0 to 7.5 can affect the rate of the membrane fusion notably. Using a continual model, we demonstrated that the key factor defining the height of the energy barrier is the spontaneous curvature of the lipid monolayer. Changes of this parameter are likely to be caused by rearrangements of the polar part of lipid molecules in response to changes of the pH of the aqueous solution bathing the membrane. Full article
(This article belongs to the Special Issue Membrane Fusion)
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17 pages, 3120 KiB  
Article
CD9 and CD81 Interactions and Their Structural Modelling in Sperm Prior to Fertilization
by Michaela Frolikova, Pavla Manaskova-Postlerova, Jiri Cerny, Jana Jankovicova, Ondrej Simonik, Alzbeta Pohlova, Petra Secova, Jana Antalikova and Katerina Dvorakova-Hortova
Int. J. Mol. Sci. 2018, 19(4), 1236; https://doi.org/10.3390/ijms19041236 - 19 Apr 2018
Cited by 27 | Viewed by 8008
Abstract
Proteins CD9 and CD81 are members of the tetraspanin superfamily and were detected in mammalian sperm, where they are suspected to form an active tetraspanin web and to participate in sperm–egg membrane fusion. The importance of these two proteins during the early stages [...] Read more.
Proteins CD9 and CD81 are members of the tetraspanin superfamily and were detected in mammalian sperm, where they are suspected to form an active tetraspanin web and to participate in sperm–egg membrane fusion. The importance of these two proteins during the early stages of fertilization is supported by the complete sterility of CD9/CD81 double null female mice. In this study, the putative mechanism of CD9/CD81 involvement in tetraspanin web formation in sperm and its activity prior to fertilization was addressed. Confocal microscopy and colocalization assay was used to determine a mutual CD9/CD81 localization visualised in detail by super-resolution microscopy, and their interaction was address by co-immunoprecipitation. The species-specific traits in CD9 and CD81 distribution during sperm maturation were compared between mice and humans. A mutual position of CD9/CD81 is shown in human spermatozoa in the acrosomal cap, however in mice, CD9 and CD81 occupy a distinct area. During the acrosome reaction in human sperm, only CD9 is relocated, compared to the relocation of both proteins in mice. The structural modelling of CD9 and CD81 homologous and possibly heterologous network formation was used to propose their lateral Cis as well as Trans interactions within the sperm membrane and during sperm–egg membrane fusion. Full article
(This article belongs to the Special Issue Membrane Fusion)
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14 pages, 6597 KiB  
Article
Charged N-terminus of Influenza Fusion Peptide Facilitates Membrane Fusion
by Remigiusz Worch, Anita Dudek, Joanna Krupa, Anna Szymaniec and Piotr Setny
Int. J. Mol. Sci. 2018, 19(2), 578; https://doi.org/10.3390/ijms19020578 - 14 Feb 2018
Cited by 7 | Viewed by 3764
Abstract
Cleavage of hemagglutinin precursor (HA0) by cellular proteases results in the formation of two subunits, HA1 and HA2. The N-terminal fragment of HA2, named a fusion peptide (HAfp), possess a charged, amine N-terminus. It has been shown that the N-terminus of HAfp stabilizes [...] Read more.
Cleavage of hemagglutinin precursor (HA0) by cellular proteases results in the formation of two subunits, HA1 and HA2. The N-terminal fragment of HA2, named a fusion peptide (HAfp), possess a charged, amine N-terminus. It has been shown that the N-terminus of HAfp stabilizes the structure of a helical hairpin observed for a 23-amino acid long peptide (HAfp1-23), whose larger activity than HAfp1-20 has been demonstrated recently. In this paper, we analyze the effect of N-terminal charge on peptide-mediated fusion efficiency and conformation changes at the membrane interface by comparison with the corresponding N-acetylated peptides of 20- and 23-amino acid lengths. We found that higher fusogenic activities of peptides with unmodified amino termini correlates with their ability to form helical hairpin structures oriented perpendicularly to the membrane plane. Molecular dynamics simulations showed that acetylated peptides adopt open and surface-bound conformation more often, which induced less disorder of the phospholipid chains, as compared to species with unmodified amino termini. Full article
(This article belongs to the Special Issue Membrane Fusion)
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15 pages, 4229 KiB  
Article
Peptide-Based Membrane Fusion Inhibitors Targeting HCoV-229E Spike Protein HR1 and HR2 Domains
by Shuai Xia, Wei Xu, Qian Wang, Cong Wang, Chen Hua, Weihua Li, Lu Lu and Shibo Jiang
Int. J. Mol. Sci. 2018, 19(2), 487; https://doi.org/10.3390/ijms19020487 - 06 Feb 2018
Cited by 54 | Viewed by 9880
Abstract
Human coronavirus 229E (HCoV-229E) infection in infants, elderly people, and immunocompromised patients can cause severe disease, thus calling for the development of effective and safe therapeutics to treat it. Here we reported the design, synthesis and characterization of two peptide-based membrane fusion inhibitors [...] Read more.
Human coronavirus 229E (HCoV-229E) infection in infants, elderly people, and immunocompromised patients can cause severe disease, thus calling for the development of effective and safe therapeutics to treat it. Here we reported the design, synthesis and characterization of two peptide-based membrane fusion inhibitors targeting HCoV-229E spike protein heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains, 229E-HR1P and 229E-HR2P, respectively. We found that 229E-HR1P and 229E-HR2P could interact to form a stable six-helix bundle and inhibit HCoV-229E spike protein-mediated cell-cell fusion with IC50 of 5.7 and 0.3 µM, respectively. 229E-HR2P effectively inhibited pseudotyped and live HCoV-229E infection with IC50 of 0.5 and 1.7 µM, respectively. In a mouse model, 229E-HR2P administered intranasally could widely distribute in the upper and lower respiratory tracts and maintain its fusion-inhibitory activity. Therefore, 229E-HR2P is a promising candidate for further development as an antiviral agent for the treatment and prevention of HCoV-229E infection. Full article
(This article belongs to the Special Issue Membrane Fusion)
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15 pages, 9518 KiB  
Article
Deciphering the Functional Composition of Fusogenic Liposomes
by Rejhana Kolašinac, Christian Kleusch, Tobias Braun, Rudolf Merkel and Agnes Csiszár
Int. J. Mol. Sci. 2018, 19(2), 346; https://doi.org/10.3390/ijms19020346 - 24 Jan 2018
Cited by 64 | Viewed by 9627
Abstract
Cationic liposomes are frequently used as carrier particles for nucleic acid delivery. The most popular formulation is the equimolar mixture of two components, a cationic lipid and a neutral phosphoethanolamine. Its uptake pathway has been described as endocytosis. The presence of an aromatic [...] Read more.
Cationic liposomes are frequently used as carrier particles for nucleic acid delivery. The most popular formulation is the equimolar mixture of two components, a cationic lipid and a neutral phosphoethanolamine. Its uptake pathway has been described as endocytosis. The presence of an aromatic molecule as a third component strongly influences the cellular uptake process and results in complete membrane fusion instead of endocytosis. Here, we systematically varied all three components of this lipid mixture and determined how efficiently the resulting particles fused with the plasma membrane of living mammalian cells. Our results show that an aromatic molecule and a cationic lipid component with conical molecular shape are essential for efficient fusion induction. While a neutral lipid is not mandatory, it can be used to control fusion efficiency and, in the most extreme case, to revert the uptake mechanism back to endocytosis. Full article
(This article belongs to the Special Issue Membrane Fusion)
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14 pages, 2247 KiB  
Article
Peptide-Mediated Liposome Fusion: The Effect of Anchor Positioning
by Niek S. A. Crone, Dirk Minnee, Alexander Kros and Aimee L. Boyle
Int. J. Mol. Sci. 2018, 19(1), 211; https://doi.org/10.3390/ijms19010211 - 10 Jan 2018
Cited by 13 | Viewed by 5165
Abstract
A minimal model system for membrane fusion, comprising two complementary peptides dubbed “E” and “K” joined to a cholesterol anchor via a polyethyleneglycol spacer, has previously been developed in our group. This system promotes the fusion of large unilamellar vesicles and facilitates liposome-cell [...] Read more.
A minimal model system for membrane fusion, comprising two complementary peptides dubbed “E” and “K” joined to a cholesterol anchor via a polyethyleneglycol spacer, has previously been developed in our group. This system promotes the fusion of large unilamellar vesicles and facilitates liposome-cell fusion both in vitro and in vivo. Whilst several aspects of the system have previously been investigated to provide an insight as to how fusion is facilitated, anchor positioning has not yet been considered. In this study, the effects of placing the anchor at either the N-terminus or in the center of the peptide are investigated using a combination of circular dichroism spectroscopy, dynamic light scattering, and fluorescence assays. It was discovered that anchoring the “K” peptide in the center of the sequence had no effect on its structure, its ability to interact with membranes, or its ability to promote fusion, whereas anchoring the ‘E’ peptide in the middle of the sequence dramatically decreases fusion efficiency. We postulate that anchoring the ‘E’ peptide in the middle of the sequence disrupts its ability to form homodimers with peptides on the same membrane, leading to aggregation and content leakage. Full article
(This article belongs to the Special Issue Membrane Fusion)
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4065 KiB  
Article
Switching between Successful and Dead-End Intermediates in Membrane Fusion
by Rodion J. Molotkovsky, Timur R. Galimzyanov, Irene Jiménez-Munguía, Konstantin V. Pavlov, Oleg V. Batishchev and Sergey A. Akimov
Int. J. Mol. Sci. 2017, 18(12), 2598; https://doi.org/10.3390/ijms18122598 - 02 Dec 2017
Cited by 18 | Viewed by 4576
Abstract
Fusion of cellular membranes during normal biological processes, including proliferation, or synaptic transmission, is mediated and controlled by sophisticated protein machinery ensuring the preservation of the vital barrier function of the membrane throughout the process. Fusion of virus particles with host cell membranes [...] Read more.
Fusion of cellular membranes during normal biological processes, including proliferation, or synaptic transmission, is mediated and controlled by sophisticated protein machinery ensuring the preservation of the vital barrier function of the membrane throughout the process. Fusion of virus particles with host cell membranes is more sparingly arranged and often mediated by a single fusion protein, and the virus can afford to be less discriminative towards the possible different outcomes of fusion attempts. Formation of leaky intermediates was recently observed in some fusion processes, and an alternative trajectory of the process involving formation of π-shaped structures was suggested. In this study, we apply the methods of elasticity theory and Lagrangian formalism augmented by phenomenological and molecular geometry constraints and boundary conditions to investigate the traits of this trajectory and the drivers behind the choice of one of the possible scenarios depending on the properties of the system. The alternative pathway proved to be a dead end, and, depending on the parameters of the participating membranes and fusion proteins, the system can either reversibly enter the corresponding “leaky” configuration or be trapped in it. A parametric study in the biologically relevant range of variables emphasized the fusion protein properties crucial for the choice of the fusion scenario. Full article
(This article belongs to the Special Issue Membrane Fusion)
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Review

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19 pages, 665 KiB  
Review
Mitochondrial Dynamics in Basal and Stressful Conditions
by Naima Zemirli, Etienne Morel and Diana Molino
Int. J. Mol. Sci. 2018, 19(2), 564; https://doi.org/10.3390/ijms19020564 - 13 Feb 2018
Cited by 114 | Viewed by 9897
Abstract
The historical role of mitochondria resides in converting the energy released during the oxidation of macromolecules (carbohydrates, lipids and proteins) into adenosine tri-phosphate, a major form of chemically stored energy which sustains cell growth and homeostasis. Beyond this role in bioenergetics regulation, mitochondria [...] Read more.
The historical role of mitochondria resides in converting the energy released during the oxidation of macromolecules (carbohydrates, lipids and proteins) into adenosine tri-phosphate, a major form of chemically stored energy which sustains cell growth and homeostasis. Beyond this role in bioenergetics regulation, mitochondria play a role in several other cellular processes including lipid metabolism, cellular calcium homeostasis, autophagy and immune responses. Furthermore, mitochondria are highly dynamic organelles: as all other cellular endomembranes, they are continuously moving along cytoskeleton, and, most importantly, they constantly interact one with each other by membrane tethering, fusion and fission. This review aims to highlight the tight correlation between the morphodynamics of mitochondria and their biological function(s), in physiological as well as stress conditions, in particular nutrient deprivation, pathogen attack and some human diseases. Finally, we emphasize some crosstalk between the fusion/fission machinery and the autophagy pathway to ending on some speculative hypothesis to inspire future research in the field. Full article
(This article belongs to the Special Issue Membrane Fusion)
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Other

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2173 KiB  
Hypothesis
A Membrane-Fusion Model That Exploits a β-to-α Transition in the Hydrophobic Domains of Syntaxin 1A and Synaptobrevin 2
by Cameron B. Gundersen
Int. J. Mol. Sci. 2017, 18(7), 1582; https://doi.org/10.3390/ijms18071582 - 21 Jul 2017
Cited by 2 | Viewed by 3736
Abstract
Parallel zippering of the SNARE domains of syntaxin 1A/B, SNAP-25, and VAMP/synaptobrevin 2 is widely regarded as supplying the driving force for exocytotic events at nerve terminals and elsewhere. However, in spite of intensive research, no consensus has been reached concerning the molecular [...] Read more.
Parallel zippering of the SNARE domains of syntaxin 1A/B, SNAP-25, and VAMP/synaptobrevin 2 is widely regarded as supplying the driving force for exocytotic events at nerve terminals and elsewhere. However, in spite of intensive research, no consensus has been reached concerning the molecular mechanism by which these SNARE proteins catalyze membrane fusion. As an alternative to SNARE-based models, a scenario was developed in which synaptotagmin 1 (or, 2) can serve as a template to guide lipid movements that underlie fast, synchronous exocytosis at nerve terminals. This “dyad model” advanced a novel proposal concerning the membrane disposition of the palmitoylated, cysteine-rich region of these synaptotagmins. Unexpectedly, it now emerges that a similar principle can be exploited to reveal how the hydrophobic, carboxyl-terminal domains of syntaxin 1A and synaptobrevin 2 can perturb membrane structure at the interface between a docked synaptic vesicle and the plasma membrane. These “β-to-α transition” models will be compared and contrasted with other proposals for how macromolecules are thought to intervene to drive membrane fusion. Full article
(This article belongs to the Special Issue Membrane Fusion)
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