Membrane fusion in eukaryotic cells mediates the biogenesis of organelles, vesicular traffic between them, and exo- and endocytosis of important signalling molecules, such as hormones and neurotransmitters. Distinct tasks in intracellular membrane fusion have been assigned to conserved protein systems. Tethering proteins mediate the initial recognition and attachment of membranes, whereas SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein complexes are considered as the core fusion engine. SNARE complexes provide mechanical energy to distort membranes and drive them through a hemifusion intermediate towards the formation of a fusion pore1,2,3. This last step is highly energy-demanding4,5. Here we combine the in vivo and in vitro fusion of yeast vacuoles with molecular simulations to show that tethering proteins are critical for overcoming the final energy barrier to fusion pore formation. SNAREs alone drive vacuoles only into the hemifused state. Tethering proteins greatly increase the volume of SNARE complexes and deform the site of hemifusion, which lowers the energy barrier for pore opening and provides the driving force. Thereby, tethering proteins assume a crucial mechanical role in the terminal stage of membrane fusion that is likely to be conserved at multiple steps of vesicular traffic. We therefore propose that SNAREs and tethering proteins should be considered as a single, non-dissociable device that drives fusion. The core fusion machinery may then be larger and more complex than previously thought.
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We thank V. Comte and J. Gao for the purification of proteins and antibodies. This work was supported by grants from the DFG (SFB 944, to C.U.), State of Lower Saxony (life@nano, to H.J.R) and SNF and ERC to A.M. HLRN is acknowledged for CPU time.
The authors declare no competing financial interests.
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Extended data figures and tables
a, ypt7Δ vacuoles lack HOPS. Ypt7 and HOPS content of total cell extracts and purified vacuoles from wild-type and ypt7Δ mutants in BJ3505 and DKY6281 cells, representing the background strains used for the content mixing assay. b, Purified HOPS, HOPS subcomplexes and CORVET. The complexes used for the in vitro experiments were analysed by SDS–PAGE and Coomassie staining. The gel represents the preparations, which followed published routine procedure, used for the experiments in Fig. 1 and Extended Data Figs 3 and 4. c, Production of Fab fragments from polyclonal antibodies to Vam3 and Nyv1. Schematic view of papain cleavage sites for Fab fragment generation (left). Affinity-purified antibodies and Fab fragments extracted after papain digestion were analysed by non-reducing SDS–PAGE and Coomassie staining. The gel shows the preparation used in Fig. 2. d, Expression of FKBP and FRB fusion proteins. Total cell extracts were prepared from 0.1 OD600 nm units of logarithmic cultures of yeast strains expressing Vam7–2×FKBP12 and/or Pfk1–FRB–GFP. Proteins were analysed by SDS–PAGE and western blotting against Vam7, Vam3 and GFP. e, As in d, but for cells expressing Vam7–LL–2×FKBP12, containing the 35-amino-acid linker. For a and c–e, similar results were obtained from two independent preparations.
Extended Data Figure 2 Kinetics and efficiency of in vitro vacuole fusion, measured by content mixing.
Vacuoles were prepared from two different strains, which contain either the soluble 45-kDa maturase Pep4 (contained in DKY6281) or the pro-alkaline phosphatase (p-ALP) (contained in BJ3505). Formation of a sufficiently large fusion pore allows Pep4 to transfer into the p-ALP containing fusion partner, leading to proteolytic cleavage of its pro-sequence and activation of the enzyme (m-ALP). This activity is used as a measurement of fusion. Note that proteolytic maturation of p-ALP is fast and not limiting for the development of the content mixing signal46. Standard fusion reactions were started, and aliquots were withdrawn at the indicated time points and set on ice. a, At the end of the 60 min period, m-ALP activity was determined for all samples. Data are means ± s.d. from 3 biologically independent experiments. b, Aliquots from one of the experiments in (a) were trichloroacetic acid (TCA)-precipitated and analysed by SDS–PAGE and western blotting against ALP and Vam3. Signals were detected on a LICOR infrared scanner (left) and quantified (right) as the ratio of m-ALP to (m-ALP + p-ALP). Vam3 has been included as a loading control. Note that after one round of fusion, only a maximum of 50% of p-ALP can be matured, because half of the fusion events in the suspension will occur between like vacuoles (that is, Pep4/Pep4 or p-ALP/p-ALP) and will not produce a signal.
Two-stage fusion reactions with ypt7Δ vacuoles were run as in Fig. 1g, in the absence of ATP. rVam7 had been added in the first phase of the incubation (1°), and either 0.4 μM HOPS subcomplexes or 0.4 μM CORVET was added during the second incubation (2°). Half of the samples also received 6% Ficoll-400, an agent mimicking molecular crowding35, during the second incubation. At the end of the 75-min incubation period, content mixing was assayed. Fusion activity of a standard wild-type reaction performed in the presence of ATP served as a100% reference. Data are mean ± s.d. from 3 biologically independent experiments.
Two-stage fusion reactions were run as in Fig. 1g in the presence or absence of ATP. rVam7 was added in the first phase of the incubation, HOPS was added only in the only in the second incubation. At the end of the 75-min incubation period, content mixing was assayed. Data are mean ± s.d. from 3 biologically independent experiments.
Extended Data Figure 5 A molecular crowding agent cannot stimulate fusion in the absence of bulky SNARE ligands.
Two-stage fusion reactions with ypt7Δ vacuoles were run as in Fig. 2b, in the absence or presence of ATP. rVam7 was added in the first phase of the incubation where indicated, antibodies and various concentrations of the crowding agent Ficoll-400 were added only during the second incubation. At the end of the 75-min incubation period, content mixing was assayed. Fusion activity of a wild-type reaction performed in the presence of ATP served as a 100% reference. Data are mean ± s.d. from 3 biologically independent experiments.
Extended Data Figure 6 Effect of rapamycin-induced dimerization on in vivo vacuole fusion using the small fusion protein FRB–GFP.
a, Schematic view of rapamycin-induced FKBP12/FRB-tagged protein dimerization between Vam7–2×FKBP12 and FRB–GFP. b, Logarithmically growing cells, expressing tagged Vam7–2×FKBP12, were stained with the vacuole tracer FM4-64 and analysed by spinning disc microscopy before and 10 min after the addition of 10 μM rapamycin. Scale bar, 5 μm. Similar results were obtained in 3 biologically independent repetitions.
Extended Data Figure 7 Fusion can be prematurely triggered by protein recruitment after osmotically induced vacuole fragmentation.
a, Logarithmically growing cells, carrying Vam7–2×FKBP12 and Pfk1–FRB–GFP as indicated, were stained with the vacuole tracer FM4-64. Vacuole fission was induced by adding 0.5 M NaCl. Cells were analysed by spinning disc microscopy before and 10 and 60 min after salt addition. The cells were grouped into three categories according to the number of vacuoles visible per cell. 100 cells were analysed per sample. b, As in a, but 10 μM rapamycin was added before the salt shock. c, As in b, but with cells expressing non-tagged Vam7. Data are mean ± s.d. from 3 biologically independent experiments. Scale bars, 5 μm.
This plot complements Fig. 4. a, The free energy barrier of fusion pore opening is derived for a simulated system consisting of three SNARE complexes (right) and a POPC membrane that contains 40% POPE (coloured orange). To this aim, we pull two hydrophilic probes (coloured purple) towards the centre of the stalk and estimate the work (ΔG) as a function of probe–probe distance (the stalk thickness)32. The arrows in the free energy profile indicate the nucleation barrier for the fusion pore. Beyond this stage, subsequent pore opening proceeds in the absence of additional work (the plateau region). Tethering complexes such as HOPS are attracted to the membrane by Rab-GTPases or through direct lipid interaction10,47. An attractive HOPS surface (green line) conserves the lowered nucleation barrier, even when the surface attractions fully compensate the membrane bending energy (no net bending work; Extended Data Fig. 9). Error bars are calculated via Bayesian resampling of 50 overlapping WHAM histograms42 Each parental WHAM histogram consists of more than 30,000 data points (autocorrelation up to approximately 1,500 data points). b, Pore formation in the absence of HOPS. A defect is frequently formed in the vicinity of the SNARE TMDs (black arrow), illustrating the presence of a high stress (the defect probably decreases the bending stress). Fusion pore formation is associated with a sudden reduction of the sharp curvature near the circumference of the stalk (dashed lines). Fusion pores tend to adopt a teardrop shape48,49. c, Fusion pore formation in the presence of HOPS. The pre-existing teardrop membrane shape imposed by HOPS likely provides a geometrical and therefore an energetic advantage for pore formation. d, Set up in which we artificially enforced formation of a leakage pore/defect in the direct vicinity of the stalk (the rationale behind this has been previously explained32). The induced defect (between 3.2 and 1.8 nm the probe pierced through the membrane) instantaneously recovers. This suggests that the stress that HOPS imposes on the fusion site does not prime fusion to become leaky.
Extended Data Figure 9 Detailed analysis of HOPS-mediated membrane bending in the presence of an inter-membrane restraint.
a, Simulation snapshot illustrating the geometry of the system. Shown is the central plane of the membrane (the lipid tail ends), the stalk, and HOPS. The SNARE complex present in the simulation setup is not illustrated. This setup serves as a motivation for the elastic continuum model. b, Bending work required to place HOPS at the (hemi-)fusion site and peristaltic force experienced by HOPS. Simulations were run to measure the work required to place HOPS-like spheres of 10–14 nm diameter at the site of hemifusion or at a fusion pore (FP). HOPS could be detached from the SNARE complex by a long spacer (link.). The influence of a SNARE complex with an unstructured, non-helical juxta-membrane region (unstr.) and of a HOPS mimic that was attractive to the membrane surface (attr.) was also analysed. The bottom panel shows averages obtained from the simulations. fd is the (peristaltic) force that pushes HOPS away from the inter-membrane restraint (for example, a stalk, fusion pore, or trans-SNARE complex). Note that surface attractions or Rab-GTPase interactions of HOPS (modelling the tethering of membranes)10,47 can yield a negative value of the average work required to bend the membrane (bending occurs spontaneously). Fusion pore formation reduces the required bending work—it moves HOPS away from the restraint because of additional SNARE association up into the TMD region. The errors in the averages are derived from block averaging over more than 10,000 data points until the error becomes independent of block size (autocorrelation up to approximately 300 data points). c, Elastic continuum model. The coordinate system is based on the snapshot of the molecular dynamics simulation shown in a. Because of symmetry along the x–y plane and x–z plane, we only model one-quarter of the original system. The cartoon illustrates the shape of minimal free energy for a membrane (modelled by a single sheet), subjected to two constraints: (1) A local constraint on the position (height) of the membrane illustrated by the black arrow at z = 2 nm. This mimics the inter-membrane constraint (stalk, fusion pore or partly-assembled SNARE complex). (2) The presence of a hemisphere, this mimics HOPS. The colour code illustrates the height of the membrane (the z axis) relative to the two constraints. d, Prediction of bending energies by the elastic continuum model. The bending energy is shown as a function of the size and distance of HOPS to the inter-membrane restraint. Top, bending energy decreases steeply when HOPS moves away from the restraint. The predicted values are about a factor of two lower than the ‘bending work’ predicted by the simulations (see Methods). Middle, the corresponding peristaltic force (fd) on HOPS (the derivative of bending energy). At short distances, fd becomes substantial (tens of pN). Note that making the surface of HOPS moderately attractive to the membrane affects fd only weakly, that is, it does not result in an attraction towards the stalk. Bottom, the relative reduction of membrane area as a result of HOPS-induced membrane bending. This property reflects the tension that HOPS induces by curving the membrane near the contact zone. In contrast to bending energy and force, tension only weakly depends on the distance (d) to the restraint.
a, One way of rationalizing the acceleration of fusion pore formation by a SNARE complex is to consider it as a mechanical device that exerts force on the luminal leaflets through its TMDs, thereby compressing the stalk. This can happen through a peristaltic force that pulls the SNARE complex away from the stalk, or through the elastic bending of the SNAREs. This latter mode of force transmission requires the juxta-membrane regions, which connect the coiled-coil domains of the SNAREs to their TMDs, to be structured and rigid. The compressing force that the SNARE complex exerts on the stalk can be rationalized from the apparent work (free energy) that one needs to perform in order to force the luminal C termini of Vam3 and Nyv1 in closer proximity. We estimated how HOPS binding affects the force that the C termini of the SNAREs Vam3 and Nyv1 exert on the stalk. b, The work required to slightly indent the stalk in the presence of repulsive or attractive HOPS-spheres of different diameter has been determined. It is shown relative to the situation without the sphere. Error bars are calculated via Bayesian resampling of 15 overlapping WHAM histograms42. Each parental WHAM histogram is comprised of more than 30,000 data points (autocorrelation up to approximately 1,200 data points). The lines shown result from fitting a power expansion (up to the fourth power) through the average of each data point. Error bars are calculated via Bayesian resampling of 15 overlapping WHAM histograms44. c, The corresponding forces on the SNARE TMDs were derived from this work. Apparent gains in the force exerted by the SNARE C termini (left) are shown as a function of their distance in the hemifusion structure. HOPS binding can double or triple the magnitude of the apparent force (10–20 pN) that a SNARE complex exerts on a stalk50. The gain dissipates, however, as zipping of the SNARE TMDs progresses and their C termini approach each other. d, Snapshots of three special scenarios. Top, The HOPS sphere is placed at a distal location with respect to the stalk (for example, via attachment with a flexible linker), which abolishes the force gain. Middle, A sphere that favourably attracts (and bends) the membrane, this conserves the force gain. Bottom, unstructured, flexible SNARE juxta-membrane regions partially disrupt the mechanical coupling between the coiled-coil domains and the TMDs; they decrease the apparent gain in SNARE pull force induced by HOPS. Structured (α-helical) SNARE juxta-membrane regions result in a high initial force gain which gradually reduces. In contrast, unstructured, flexible juxta-membrane regions, which impair vacuole fusion51, result in a near-constant force gain of only about 8 pN. Both cases converge to similar force values when the C termini of Vam3 and Nyv1 come in closer proximity. Because the SNARE complex is unable to exert bending force on the membrane, when the connection between its transmembrane anchors and the SNARE domains is completely flexible, we relate the remaining gain to an effective softening of the stalk because of the induced membrane curvature and to the peristaltic force generated by the interaction of the HOPS sphere with the SNAREs.
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D’Agostino, M., Risselada, H., Lürick, A. et al. A tethering complex drives the terminal stage of SNARE-dependent membrane fusion. Nature 551, 634–638 (2017). https://doi.org/10.1038/nature24469
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