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Membrane Bending by Protein–Protein Crowding Jeanne C LETTERS Membrane bending by protein–protein crowding Jeanne C. Stachowiak1,2,9,10, Eva M. Schmid3,9,10, Christopher J. Ryan4, Hyoung Sook Ann3, Darryl Y. Sasaki2, Michael B. Sherman5, Phillip L. Geissler4,6,7, Daniel A. Fletcher3,4,8,10 and Carl C. Hayden2,10 Curved membranes are an essential feature of dynamic cellular to bend membranes through a wedge-like mechanism5,6. Clathrin- structures, including endocytic pits, filopodia protrusions mediated endocytosis, the main endocytic pathway in eukaryotic and most organelles1,2. It has been proposed that specialized cells, requires a network of interacting proteins, several of which proteins induce curvature by binding to membranes through two have been implicated in membrane bending12. Central among these, primary mechanisms: membrane scaffolding by curved proteins epsin1 is thought to be capable of driving curvature generation in or complexes3,4; and insertion of wedge-like amphipathic clathrin-coated pits5. Our work tests the presently accepted hypothesis helices into the membrane5,6. Recent computational studies that epsin1 bends membranes by helix insertion and finds instead that have raised questions about the efficiency of the helix-insertion protein–protein crowding drives membrane bending. mechanism, predicting that proteins must cover nearly The amino-terminal homology region of epsin1 (ENTH domain) 100% of the membrane surface to generate high curvature7–9, attaches to the membrane by binding phosphatidylinositol-4,5- an improbable physiological situation. Thus, at present, we lack bisphosphate (PtdIns(4,5)P2) lipids and inserting an amphipathic helix a sufficient physical explanation of how protein attachment (helix0) into its cytoplasmic leaflet5. Epsin1 has been shown to have a bends membranes efficiently. On the basis of studies of epsin1 cargo sorting role13, to act as a curvature sensor14 and to bind multiple and AP180, proteins involved in clathrin-mediated endocytosis, endocytic proteins through its flexible carboxy terminus15, all of which we propose a third general mechanism for bending fluid probably assist in its localization to endocytic sites. As the ENTH cellular membranes: protein–protein crowding. By correlating domain has no inherent curvature with which to influence membrane membrane tubulation with measurements of protein densities shape, it has been thought that insertion of helix0 increases the mem- on membrane surfaces, we demonstrate that lateral pressure brane’s outer leaflet area, causing convex curvature. This hypothesis, generated by collisions between bound proteins drives bending. originally proposed for the epsin1 ENTH domain and subsequently Whether proteins attach by inserting a helix or by binding termed hydrophobic insertion, has been used to explain the role of lipid heads with an engineered tag, protein coverage above amphipathic insertion motifs in proteins relevant to a wide range of 20% is sufficient to bend membranes. Consistent with this topics in cell biology, including viral entry16, apoptosis17, autophagy18, ⇠ crowding mechanism, we find that even proteins unrelated to vesicular traffic6 and motility19. Supporting this hydrophobic insertion membrane curvature, such as green fluorescent protein (GFP), hypothesis, the N-terminal homology domain of AP180 (ANTH can bend membranes when sufficiently concentrated. These domain), which is structurally similar to the ENTH domain but missing findings demonstrate a highly efficient mechanism by which the helix, has not been found to generate curvature20. the crowded protein environment on the surface of cellular Although helix insertion is expected to increase the area of one leaflet membranes can contribute to membrane shape change. of the bilayer, it is unclear whether that increase is sufficient to generate high curvatures, given that helix density is limited by the size and Highly curved cellular membranes are thought to form by two distinct coverage of the protein containing the helix7,9. Recently, continuum mechanisms. First, intrinsically curved proteins4 and oligomers3 can models7 and molecular dynamics simulations8 have predicted that helix drive bending, although their ability to do so independently has insertions alone must occupy 10–25% of the membrane surface area been debated10,11. Second, insertion of amphipathic helices is thought to generate the curvatures found in endocytic structures. For epsin1 1The University of Texas at Austin, Department of Biomedical Engineering, Austin, Texas 78712, USA. 2Sandia National Laboratories, Livermore, California 94551, USA. 3Department of Bioengineering, University of California, Berkeley, California 94720, USA. 4Biophysics Gradate Group, University of California, Berkeley, California 94720, USA. 5Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA. 6Department of Chemistry, University of California, Berkeley, California 94720, USA. 7Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. 8Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. 9These authors contributed equally to this work. 10Correspondence should be addressed to J.C.S., E.M.S., D.A.F. or C.C.H. (e-mail: [email protected] or [email protected] or fl[email protected] or [email protected]) Received 7 October 2011; accepted 12 July 2012; published online 19 August 2012; DOI: 10.1038/ncb2561 944 NATURE CELL BIOLOGY VOLUME 14 NUMBER 9 SEPTEMBER 2012 | | © 2012 Macmillan Publishers Limited. All rights reserved. LETTERS a b high PtdIns(4,5)P2 concentrations, produced protein-coated lipid tubules that frequently consumed much of the domain area (Fig. 1b). Tubules had diffraction-limited diameters and seemed highly flexible, fluctuating rapidly in conformation (Supplementary Movie S1) and often exhibiting a pearled morphology, indicative of an increase in spontaneous curvature22 (Supplementary Fig. S2a–c). Similar tubules were observed for alternative systems of fluid lipids that also contained PtdIns(4,5)P2, both with and without phase-separated domains, showing that this behaviour is not limited to the chosen lipid mixture (Supplementary Fig. S1e,f). In our experiments, the percentage of vesicles having observable tubules was found to depend strongly on the molar fraction of PtdIns(4,5)P2 included in the membrane domain, increasing from 9 4% s.d. (for 0.5 mol% ± PtdIns(4,5)P ) to 84 5% s.d. (with 20 mol% PtdIns(4,5)P , Fig. 1c). 2 ± 2 c As expected, no protein attachment to membranes was observed in the 100 Epsin1 ENTH absence of PtdIns(4,5)P2. 80 We determined the density of membrane-bound proteins re- f vesicles 60 Helix0 sponsible for the observed tubulation by measuring FRET between ing tubes 40 dye-labelled proteins on the membrane surface. Using this assay, we PtdIns(4,5)P2 form 20 quantified the percentage of the membrane covered by wtENTH as 0 Percentage o 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 22.5 Lipid bilayer a function of increasing PtdIns(4,5)P2 concentration (Fig. 2c and Percentage of PtdIns(4,5)P2 in domain Supplementary Fig. S3). Separate donor- and acceptor-labelled protein populations mixed in a 1:5 ratio (1 µM total wtENTH) were exposed Figure 1 PtdIns(4,5)P2 concentration in membranes controls the frequency to the same GUVs used for determining the frequency of tubulation of lipid tubule formation by epsin1. GUV composition: 12.5 mol% fluid-phase (0.5–20 mol% PtdIns(4,5)P2 in domains). As the overall protein lipids (DPhPC + 0.5–20 mol% PtdIns(4,5)P2 in domains)/40% DPPC/47.5% cholesterol. Wide-field fluorescence micrographs, all scale bars are 10 µm surface density was increased, by increasing the concentration of (red channel, Nile red; green channel, Atto488–wtENTH). (a) A domain PtdIns(4,5)P2, the density of acceptors around each donor increased, without tubules ( 2 mol% PtdIns(4,5)P ,1µM wtENTH). (b) A tubulated ⇠ 2 leading to quenching of the donor fluorescence through FRET to the domain ( 20 mol% PtdIns(4,5)P ,1µM wtENTH). (c) Percentage of vesicle ⇠ 2 acceptors (Fig. 2a,b). The donor and acceptor lifetimes were recorded domains forming tubules as a function of PtdIns(4,5)P2 concentration in domains. The error bars are the first s.d. from three independent experiments using confocal FLIM microscopy, providing images of local donor on separate vesicle batches, each with 100 vesicles categorized (N 3). ⇠ = lifetimes. If protein oligomerization occurred, we would expect to see short lifetimes even at moderate densities. However, our experiments ENTH, however, the helix insertion ( 8 Å wide 20 Å long 1.6 nm2) are accurately modelled by a random distribution of proteins at ⇠ ⇥ ⇡ takes up at most 10% of the ENTH domain’s membrane footprint all densities, which indicates no evidence of oligomerization, in ( 40 Å 40 Å 16 nm2, Supplementary Fig. S1a). Therefore, even in contrast to a recent report23. ⇠ ⇥ ⇡ the physiologically unlikely case that these proteins cover 100% of the We found that the average coverage area increased linearly membrane surface, the helix can occupy at most 10% of the membrane from 8 3% s.d. coverage (1 protein every 200 nm2) at 0.5 mol% ± surface area, still at the lower end of the helix density that computational PtdIns(4,5)P to 29 3% s.d. coverage (1 protein every 50 nm2) at 2 ± models estimate is required to drive high curvatures. Furthermore, the 5 mol% PtdIns(4,5)P2 and that coverage area increased more slowly maximum helix density is even less if the significantly larger full-length up to 45 4% s.d. coverage (1 protein every 32 nm2) at 20 mol% ± epsin1 protein is considered. PtdIns(4,5)P2, probably owing to saturation of the membrane surface As epsin1 ENTH has been shown to generate high curvatures in vitro, with proteins24. Combining these data with the measurements in we set out to measure the surface coverage required. We exposed elec- Fig. 1c reveals a strong correlation between the frequency of tubule troformed giant unilamellar vesicles (GUVs) to wild-type epsin1 ENTH formation and the percentage of the membrane domain area covered (wtENTH) and quantified the percentage of vesicles forming tubules.
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