The Principle of Membrane Fusion in the Cell (Nobel Lecture)

Rothman, James E.

doi:10.1002/anie.201402380

Cited by 136 publications

(127 citation statements)

References 53 publications

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“…Synaptobrevins (eg, Vamp1, Vamp2), syntaxins, and the synaptosomal‐associated protein Snap25 represent the main components of the SNARE (soluble N ‐ethylmaleimide‐sensitive factor attachment protein receptors) complex, which is involved in docking and fusion of synaptic vesicles with the presynaptic membrane at the central and the neuromuscular synapses 15, 16. Proteins belonging to this complex are involved in vesicle docking through the evolutionarily conserved active v‐SNARE coiled coil homology domain and present high sequence similarity across the different SNAREs 17, 18, 19…”

Section: Discussionmentioning

confidence: 99%

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

Salpietro

Lin

Vedove³

et al. 2017

Annals of Neurology

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We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1 lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597–603

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Section: Discussionmentioning

confidence: 99%

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

Salpietro

Lin

Vedove³

et al. 2017

Annals of Neurology

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“…We show by mutagenesis that membrane binding of the N-terminal domain is essential for activation of Ca 2+ -triggered fusion. Consistent with the membrane-binding property, the N-terminal domain can be substituted by the influenza virus hemagglutinin fusion peptide, and this chimera also activates Ca (1,2). Synaptic vesicle fusion is orchestrated by the neuronal soluble N-ethylmaleimidesensitive factor attachment protein receptor (SNARE) fusion proteins (3,4), in conjunction with synaptotagmin, complexin, and other synaptic proteins.…”

Section: +mentioning

confidence: 94%

N-terminal domain of complexin independently activates calcium-triggered fusion

Lai

Choi

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Complexin activates Ca 2+-triggered neurotransmitter release and regulates spontaneous release in the presynaptic terminal by cooperating with the neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and the Ca 2+ -sensor synaptotagmin. The N-terminal domain of complexin is important for activation, but its molecular mechanism is still poorly understood. Here, we observed that a split pair of N-terminal and central domain fragments of complexin is sufficient to activate Ca 2+ -triggered release using a reconstituted single-vesicle fusion assay, suggesting that the N-terminal domain acts as an independent module within the synaptic fusion machinery. The N-terminal domain can also interact independently with membranes, which is enhanced by a cooperative interaction with the neuronal SNARE complex. We show by mutagenesis that membrane binding of the N-terminal domain is essential for activation of Ca 2+ -triggered fusion. Consistent with the membrane-binding property, the N-terminal domain can be substituted by the influenza virus hemagglutinin fusion peptide, and this chimera also activates Ca -triggered release (5-8). Neuronal SNARE proteins form a ternary complex consisting of synaptobrevin/vesicle-associated membrane protein (VAMP2), syntaxin, and synaptosomal-associated protein 25 (SNAP-25). The main isoform synaptotagmin-1 is involved in synchronous release, and forms a conserved Ca 2+ -independent interface with the ternary SNARE complex (9), along with Ca 2+

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“…These compartments have their own function and integrity but nevertheless need to communicate with one another. A common pathway by which exchanges can occur between them is membrane fusion, a crucial process leading to the opening of a fusion pore connecting two compartments and allowing their respective contents to mix or react (1,2). The global effective activation energy of the process must be large enough to avoid frequent spontaneous membrane fusion events.…”

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confidence: 99%

Low energy cost for optimal speed and control of membrane fusion

François-Martin

Rothman

Pincet

2017

Proc. Natl. Acad. Sci. U.S.A.

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Membrane fusion is the cell's delivery process, enabling its many compartments to receive cargo and machinery for cell growth and intercellular communication. The overall activation energy of the process must be large enough to prevent frequent and nonspecific spontaneous fusion events, yet must be low enough to allow it to be overcome upon demand by specific fusion proteins [such as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs)]. Remarkably, to the best of our knowledge, the activation energy for spontaneous bilayer fusion has never been measured. Multiple models have been developed and refined to estimate the overall activation energy and its component parts, and they span a very broad range from 20 k B T to 150 k B T, depending on the assumptions. In this study, using a bulk lipid-mixing assay at various temperatures, we report that the activation energy of complete membrane fusion is at the lowest range of these theoretical values. Typical lipid vesicles were found to slowly and spontaneously fully fuse with activation energies of ∼30 k B T. Our data demonstrate that the merging of membranes is not nearly as energy consuming as anticipated by many models and is ideally positioned to minimize spontaneous fusion while enabling rapid, SNARE-dependent fusion upon demand. partments delimited by a membrane. These compartments have their own function and integrity but nevertheless need to communicate with one another. A common pathway by which exchanges can occur between them is membrane fusion, a crucial process leading to the opening of a fusion pore connecting two compartments and allowing their respective contents to mix or react (1, 2). The global effective activation energy of the process must be large enough to avoid frequent spontaneous membrane fusion events. Nevertheless, it must remain sufficiently low so that proteins like soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) (3-5) are able to overcome it and induce fusion. If multiple models (6-16) have been developed and refined to estimate this activation energy, there is still a lack of experimental data to provide its actual value and validate these models. Activation energies have been reported between intermediate states of the fusion process (17) or with nonphospholipid surfactants (18). They were obtained with nonspontaneous fusion triggered by an external source such as osmotic pressure or mechanical shear.Here, by using a minimal membrane model system, we show that the activation energy of complete and spontaneous membrane fusion is in the lowest range of the predicted values. Lipid vesicles composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) were found to slowly and spontaneously fully fuse with respective activation energies of 26.4 ± 1 k B T and 34.3 ± 0.8 k B T. Our data demonstrate that the merging of membranes is not as energy consuming as anticipated in the early models.Whereas key aspects of the transition sta...

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The Principle of Membrane Fusion in the Cell (Nobel Lecture)

Abstract: Cells contain small membrane-enclosed vesicles which transport many kinds of cargo between the compartments of the cell. The result is a choreographed program of secretory, biosynthetic, and endocytic protein traffic that serves the cell's internal physiologic needs.

Cited by 136 publications

References 53 publications

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

Homozygous mutations in VAMP1 cause a presynaptic congenital myasthenic syndrome

N-terminal domain of complexin independently activates calcium-triggered fusion

Low energy cost for optimal speed and control of membrane fusion

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