A Reduced SNARE Model for Membrane Fusion

Marsden, Hana Robson; Elbers, Nina A.; Bomans, Paul H. H.; Sommerdijk, Nico A. J. M.; Kros, Alexander

doi:10.1002/ange.200804493

Cited by 55 publications

(64 citation statements)

References 34 publications

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“…[3] Inspired by the geometry of the SNARE complex, we recently introduced a minimalistic membrane fusion concept, which utilizes hybridization between synthetic oligonucleotides anchored in disjoined membranes via terminal cholesterol (CH) groups. [4,5] Both lipid and content mixing of suspended phospholipid vesicles were equally efficient, as previously observed with SNARE proteins, [6,7] other recognition motifs like lipidated oligopeptides, [8] oligonucleotides, [9] polyethylene glycol (PEG), [10] and Ca 2 + in combination with anionic lipids. [11] Spontaneous membrane fusion has also been used for the retroactive delivery of membrane proteins to preformed supported lipid bilayers (SLBs).…”

Section: Introductionsupporting

confidence: 64%

Site‐Specific DNA‐Controlled Fusion of Single Lipid Vesicles to Supported Lipid Bilayers

et al. 2010

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We investigate the Ca(2+)-triggered fusion of lipid vesicles site-selectively tethered to a DNA-modified supported lipid bilayer array, with the DNA strands designed such that hybridization occurs in a zipperlike fashion. Prior to the addition of Ca(2+), which is observed to induce docking and subsequent fusion (within 200 ms), the vesicles display lateral mobility determined by the number of tethers. Fusion is observed to require around ten DNA strands per vesicle, but does not occur at higher DNA coverage. However, despite the fact that fusion was restricted to occurring for vesicles tethered with around ten DNA strands, there is no correlation between single-vesicle diffusivity and fusogenicity. A possible scenario for the DNA-induced fusion machinery, consistent with these observations, is that prior to Ca(2+)-induced docking, the vesicles diffuse with a small number (2-4) of DNA tethers. Upon addition of Ca(2+), the vesicles dock, presumably due to bridging of lipid head groups. Fusion then occurs under conditions where 10-16 DNA tethers form and rearrange at the rim of the contact region between a docked vesicle and the SLB. The time required for this rearrangement, which may include both DNA hybridization and dehybridization during zipping, is expected to represent the observed docking and fusion time of less than 200 ms.

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Section: Introductionsupporting

confidence: 64%

Site‐Specific DNA‐Controlled Fusion of Single Lipid Vesicles to Supported Lipid Bilayers

et al. 2010

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“…We use the computational flexibility to assess several anticipated key factors independently, investigating their function in the general locking and membrane destabilization mechanisms. Our starting point is the lipopeptide anchored to a membrane, with a lipid/cholesterol composition that matches the experimental conditions [3].…”

Section: Introductionmentioning

confidence: 99%

“…One way to reduce the complexity of this task is to introduce a simplified model system that contains only necessary ingredients for biomimetic fusion. Recently Kros [2,3] introduced such a model system with desired fusion characteristics, both lipid and content mixing [3], that holds a promise for targeted drug delivery. This model system consists of liposomes that are decorated with fusogenic lipopeptides LPE or LPK, containing short peptide domains E: (EIAALEK) 3 and K: (KIAALKE) 3 that induce fusion via an unresolved mechanism that involves peptide self-assembly into E/K coiled-coils.…”

Section: Introductionmentioning

confidence: 99%

“…Recently Kros [2,3] introduced such a model system with desired fusion characteristics, both lipid and content mixing [3], that holds a promise for targeted drug delivery. This model system consists of liposomes that are decorated with fusogenic lipopeptides LPE or LPK, containing short peptide domains E: (EIAALEK) 3 and K: (KIAALKE) 3 that induce fusion via an unresolved mechanism that involves peptide self-assembly into E/K coiled-coils. Even for such a simplified fusion model, fundamental understanding is hampered by several unknowns: the protein secondary and quaternary transformations during self-assembly and membrane fusion, the protein interaction with the bilayer and the role of the solvent (e.g.…”

Section: Introductionmentioning

confidence: 99%

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Computational insight in the role of fusogenic lipopeptides at the onset of liposome fusion

Bulacu¹,

Sevink²

2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

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We performed an extensive computational study to obtain insight in the molecular mechanisms that take place prior to membrane fusion. We focused on membrane-anchored hybrid macromolecules (lipid–polymer–oligopeptide) that mimic biological SNARE proteins in terms of liposome fusion characteristics [H. Robson Marsden et al., 2009]; efficient micro-second simulation was enabled by combining validated MARTINI force fields for the molecular building blocks in coarse-grained molecular dynamics (CGMD). We find that individual peptide domains in the hybrid macromolecules bind and partially integrate parallel to the membrane surface, in agreement with experimental findings. By varying several experimental design parameters, we observe that peptide domains remain in the solvent phase only in two cases: (1) for solitary lipopeptides (low concentration), below a threshold area per lipid in the membrane, and (2) when the lipopeptide concentration is high enough for the peptide domains to self-assemble into tetrameric homo-complexes. The peptide-membrane binding is not affected by solvent-induced peptide unfolding, which we mimicked by relaxing the usual MARTINI helix constraints. Remarkably, in this case, a reverse transition to a helical secondary structure is observed after binding, highlighting the role of the membrane as a template (partitioning-folding coupling). Our findings undermine the current view of the initial stages towards fusion, in which membranes are thought to be kept in close apposition via dimerization of individual complementary peptides in the solvent phase. Although we did not study actual fusion, our simulations show that the formation of homomers, which is suppressed in experimental peptide pair design and therefore believed to be insignificant for fusion, by peptides anchored to the same membrane does play a key role in this locking mechanism and potentially also in membrane destabilization that precedes fusion.

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“…[5][6][7][8][9][10] We have also investigated a selective membrane fusion system based upon a sugarlike cyclic cis-diol structure on the target vesicle. [11,12] Here, we have used a well-known molecular recognition pair, phenylboronic acid derivatives and a cyclic cis-diol structure.…”

Section: Introductionmentioning

confidence: 99%

Design and Characterization of Endosomal‐pH‐Responsive Coiled Coils for Constructing an Artificial Membrane Fusion System

Kashiwada

Tsuboi

Takamura

et al. 2011

Chemistry A European J

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A weakly acidic pH-responsive polypeptide is believed to have the potential for an endosome escape function in a polypeptide-triggered delivery system. For constructing a membrane fusion device with pH-responsiveness, we have designed novel polypeptides that are capable of forming an α2 coiled coil structure. Circular dichroism spectroscopy reveals that a polypeptide, AP-LZ(EH5), with a Glu and His salt-bridge pair at a staggered position in the hydrophobic core forms a stable coiled coil structure only at endosomal pH values (pH 5.0 to 5.5). On the basis of their endosomal-pH responsiveness, a boronic acid/polypeptide conjugate (BA-H5-St) was also designed as a pilot molecule to construct a pH-responsive, one-way membrane fusion system with a sugarlike compound (phosphatidylinositol: PI)-containing liposome as a target. Membrane fusion behavior was characterized by lipid-mixing, inner-leaflet lipid-mixing, and contents-mixing assays. These studies reveal that membrane fusion is clearly observed when the pH of the experimental system is changed from 7.4 (physiological condition) to 5.0 (endosomal condition).

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A Reduced SNARE Model for Membrane Fusion

Cited by 55 publications

References 34 publications

Site‐Specific DNA‐Controlled Fusion of Single Lipid Vesicles to Supported Lipid Bilayers

Site‐Specific DNA‐Controlled Fusion of Single Lipid Vesicles to Supported Lipid Bilayers

Computational insight in the role of fusogenic lipopeptides at the onset of liposome fusion

Design and Characterization of Endosomal‐pH‐Responsive Coiled Coils for Constructing an Artificial Membrane Fusion System

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