Three SNARE complexes cooperate to mediate membrane fusion

Hua, Yuanyuan; Scheller, Richard H.

doi:10.1073/pnas.131214798

Cited by 187 publications

(159 citation statements)

References 30 publications

(43 reference statements)

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“…Because we observe this high variability with neuronal SNAREs at constant density but different curvature, a corollary of this conclusion is that we would expect that cooperativity of SNAREs involved in other trafficking pathways will also be highly variable, not because of their inherent biochemical properties, but rather owing to the particular biophysical characteristics of the trafficking vesicle. We therefore suggest that the reported estimates of numbers of involved SNARE complexes likely reflect the particular type of fusion studied and that there is no universally conserved number, as has been often assumed (13,(15)(16)(17)(18)33).…”

Section: Discussionmentioning

confidence: 89%

Variable cooperativity in SNARE-mediated membrane fusion

Hernandez

Kreutzberger

Kiessling

et al. 2014

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

101

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The soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex drives the majority of intracellular and exocytic membrane fusion events. Whether and how SNAREs cooperate to mediate fusion has been a subject of intense study, with estimates ranging from a single SNARE complex to 15. Here we show that there is no universally conserved number of SNARE complexes involved as revealed by our observation that this varies greatly depending on membrane curvature. When docking rates of small (∼40 nm) and large (∼100 nm) liposomes reconstituted with different synaptobrevin (the SNARE present in synaptic vesicles) densities are taken into account, the lipid mixing efficiency was maximal with small liposomes with only one synaptobrevin, whereas 23-30 synaptobrevins were necessary for efficient lipid mixing in large liposomes. Our results can be rationalized in terms of strong and weak cooperative coupling of SNARE complex assembly where each mode implicates different intermediate states of fusion that have been recently identified by electron microscopy. We predict that even higher variability in cooperativity is present in different physiological scenarios of fusion, and we further hypothesize that plasticity of SNAREs to engage in different coupling modes is an important feature of the biologically ubiquitous SNARE-mediated fusion reactions.M embrane fusion is an essential reaction common to intracellular trafficking and exocytosis in eukaryotic cells. Although the process involves an intricate interplay of several proteins, the fusion of membranes is dependent on the conserved family of proteins known as soluble N-ethylmaleimide-sensitive factor attachment protein receptors, or SNAREs (1, 2). In the important case of the fusion of synaptic vesicles (SVs), the SNAREs responsible are vesicular synaptobrevin 2 (syb) and plasma membrane proteins SNAP-25A (SN25) and syntaxin-1A (syx). A critical intermediate seems to be an acceptor complex consisting of a threehelix bundle formed by a 1:1 syx:SN25 complex, which serves as a binding site for syb (3,4). According to the zipper hypothesis, the N termini of syb and the 1:1 syx:SN25 complex nucleate to form a parallel four-helix bundle called the SNARE complex. The directional assembly then proceeds toward the C termini, resulting in a pulling force between the membranes that leads to their fusion (4, 5). There is some consensus that the highly exergonic nature of the assembly of the SNARE complex provides the energy for overcoming the barrier for fusion (6, 7), although identification of putative fusion intermediates at molecular resolution as well as force measurement experiments suggest multiple energy barriers are present (7-10).The question of whether and how SNAREs cooperate to mediate fusion has received substantial attention. Although some studies have left open the possibility that the number of SNARE complexes that cooperate during fusion is variable (11, 12), much attention has been given to the notion of a preferred number of SNARE complexes, ...

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Section: Discussionmentioning

confidence: 89%

Variable cooperativity in SNARE-mediated membrane fusion

Hernandez

Kreutzberger

Kiessling

et al. 2014

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

101

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“…Functional studies have clearly indicated that multiple SNARE complexes cooperate to bring about an individual vesicular fusion event (Hua and Scheller, 2001;Keller and Neale, 2001;Han et al, 2004;Keller et al, 2004;Montecucco et al, 2005), with the number of participating complexes possibly affecting the speed of opening, or the diameter of the fusion pore (Han et al, 2004). Although oligomerization may be an inherent feature of SNARE complexes, a detailed description of how such interactions take place and their relevance for membrane fusion has been lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Because PC12 cells display Ca 2ϩ -evoked secretion that requires cooperativity between three or more SNARE complexes (Hua and Scheller, 2001), expression of fulllength syb2 mutants that are incorporated into SNARE complexes of normal stability but impaired in dimer formation should generate a dominant-negative phenotype, revealing a potential role for SNARE complex dimerization in membrane fusion. PC12 cells were transfected with syb2 and hGH as described above, and intact cells were assayed directly to measure constitutive and evoked exocytosis.…”

Section: Dominant-negative Secretory Effects Of Syb2 Dimerization Mutmentioning

confidence: 99%

“…The exact number of complexes required is currently unknown, and estimates vary from three (Hua and Scheller, 2001) to five to eight (Han et al, 2004) to 10 -15 (Keller and Neale, 2001;Keller et al, 2004;Montecucco et al, 2005). Such differences may reflect the distinct experimental paradigms used and/or the types of secretory organelles studied.…”

Section: Introductionmentioning

confidence: 99%

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A Role for Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Complex Dimerization during Neurosecretion

Fdez

Jowitt

Wang

et al. 2008

MBoC

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The interactions underlying the cooperativity of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes during neurotransmission are not known. Here, we provide a molecular characterization of a dimer formed between the cytoplasmic portions of neuronal SNARE complexes. Dimerization generates a two-winged structure in which the C termini of cytosolic SNARE complexes are in apposition, and it involves residues from the vesicleassociated SNARE synaptobrevin 2 that lie close to the cytosol-membrane interface within the full-length protein.Mutation of these residues reduces stability of dimers formed between SNARE complexes, without affecting the stability of each individual SNARE complex. These mutations also cause a corresponding decrease in the ability of botulinum toxin-resistant synaptobrevin 2 to rescue regulated exocytosis in toxin-treated neuroendocrine cells. Moreover, such synaptobrevin 2 mutants give rise to a dominant-negative inhibition of exocytosis. These data are consistent with an important role for SNARE complex dimers in neurosecretion.

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“…The in vivo experimental evidence for multimerization comes from the cooperative action of the SNAREs as well as the dose dependence of inhibition by peptide blocker and the botulinum neurotoxins. Together the evidence has suggested multimers containing between 3 and 15 SNARE complexes (Han et al, 2004;Hua and Scheller, 2001;Montecucco et al, 2005;Raciborska et al, 1998;Rickman et al, 2005;Stewart et al, 2000). Nonetheless, at present working models for multimerization are quite preliminary and how they might aid in fusion is unknown.…”

Section: Snare-based Fusionmentioning

confidence: 99%

In VivoAnalysis of Membrane Fusion

Palfreyman¹,

Jørgensen²

2009

Encyclopedia of Life Sciences

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Membranes provide a barrier that allows chemical reactions to be isolated from the environment. The plasma membrane, for example, delineates self from nonself, and thus must have played an essential role in the evolution of life. Yet under numerous circumstances it is equally important that membranes be breached. Numerous forces oppose the spontaneous fusion of membranes; thus, specialized proteins have evolved to fuse membranes. The most well-understood fusion proteins are the viral fusion proteins and the SNARE proteins used in the secretory pathway. In addition, recent discoveries have lead to models for the fusion of organelles such as mitochondria and peroxisomes, as well as for cell-cell fusion. Despite the diverse structures of fusion proteins, it is possible that they function to drive membranes through a series of common lipid intermediates. Here we review the mechanisms of fusion for biological membranes, and highlight the similarities and differences in these processes.

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Three SNARE complexes cooperate to mediate membrane fusion

Cited by 187 publications

References 30 publications

Variable cooperativity in SNARE-mediated membrane fusion

Variable cooperativity in SNARE-mediated membrane fusion

A Role for Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Complex Dimerization during Neurosecretion

In VivoAnalysis of Membrane Fusion

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