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Nature of curvature coupling of amphiphysin with membranes depends on its bound density.

ABSTRACT: Cells are populated by a vast array of membrane-binding proteins that execute critical functions. Functions, like signaling and intracellular transport, require the abilities to bind to highly curved membranes and to trigger membrane deformation. Among these proteins is amphiphysin 1, implicated in clathrin-mediated endocytosis. It contains a Bin-Amphiphysin-Rvs membrane-binding domain with an N-terminal amphipathic helix that senses and generates membrane curvature. However, an understanding of the parameters distinguishing these two functions is missing. By pulling a highly curved nanotube of controlled radius from a giant vesicle in a solution containing amphiphysin, we observed that the action of the protein depends directly on its density on the membrane. At low densities of protein on the nearly flat vesicle, the distribution of proteins and the mechanical effects induced are described by a model based on spontaneous curvature induction. The tube radius and force are modified by protein binding but still depend on membrane tension. In the dilute limit, when practically no proteins were present on the vesicle, no mechanical effects were detected, but strong protein enrichment proportional to curvature was seen on the tube. At high densities, the radius is independent of tension and vesicle protein density, resulting from the formation of a scaffold around the tube. As a consequence, the scaling of the force with tension is modified. For the entire density range, protein was enriched on the tube as compared to the vesicle. Our approach shows that the strength of curvature sensing and mechanical effects on the tube depends on the protein density.

SUBMITTER: Sorre B

PROVIDER: S-EPMC3252917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Using a combination of X-ray scattering, fluorescence correlation spectroscopy, coarse-grained molecular dynamics (MD) simulations and potential of mean force calculations, we have explored the membrane remodeling effects of monomeric ?-synuclein (?S). Our initial findings from multiple approaches are that ?S (1) causes a significant thinning of the bilayer and (2) stabilizes positive mean curvature, such that the maximum principle curvature matches that of synaptic vesicles, ?S-induced tubules, and the synthetic lipid vesicles to which the protein binds most tightly. This suggests that ?S binding to synaptic vesicles likely stabilizes their intrinsic curvature. We then show that ?S induces local negative Gaussian curvature, an effect that occurs in regions of ?S shown previously via NMR and corroborated by MD simulation to have significant conformational flexibility. The induction of negative Gaussian curvature, which has implications for all curvature-sensing and curvature-generating amphipathic ?-helices, supports a hypothesis that connects helix insertion to fusion and fission of vesicles, processes that have recently been linked to ?S function. Then, in an effort to explain these biophysical properties of ?S, we promote an intrinsic curvature-field model that recasts long-range protein-protein interactions in terms of the interactions between the local curvature fields generated by lipid-protein complexes.

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Direct observation of Bin/amphiphysin/Rvs (BAR) domain-induced membrane curvature by means of molecular dynamics simulations.

Project description:The process of membrane curvature generation by BAR (Bin/amphiphysin/Rvs) domains is thought to involve the plastering of the negatively charged cell membrane to the positively charged concave surface of the BAR domain. Recent work [Peter, B. J., et al. (2004) Science, 303,495-499; Masuda, M., et al. (2006) EMBO J. 25, 2889-2897; and Gallop, J. L., et al. (2006) EMBO J. 25, 2898-2910] has demonstrated the importance of the charged, crescent-shaped surface and the N-terminal amphipathic helices (present in N-BAR domains) for generating membrane curvature. These experiments suggest that curvature is generated by the synergistic action of the N-terminal helices embedding in the lipid bilayer and the charged crescent-shaped dimer acting to "scaffold" membrane curvature. Here, we present atomistic molecular dynamics simulations that directly show membrane binding to the concave face of N-BAR domains, resulting in the generation of local membrane curvature that matches the curvature presented by the BAR domain. These simulations provide direct molecular-scale evidence that BAR domains create curvature by acting as a scaffold, forcing the membrane to locally adopt the intrinsic shape of the BAR domain. We find that BAR domains bind strongly through the maximum curvature surface and, additionally, at an orientation that presents a lesser degree of curvature, thus enabling N-BAR domains to induce a range of local curvatures. Finally, we find that the N-terminal region may play a role in biasing the orientations of N-BAR domains on the membrane surface to those that favor binding to the concave face and subsequent membrane bending.

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Roles of amphipathic helices and the bin/amphiphysin/rvs (BAR) domain of endophilin in membrane curvature generation.

Project description:Control of membrane curvature is required in many important cellular processes, including endocytosis and vesicular trafficking. Endophilin is a bin/amphiphysin/rvs (BAR) domain protein that induces vesicle formation by promotion of membrane curvature through membrane binding as a dimer. Using site-directed spin labeling and EPR spectroscopy, we show that the overall BAR domain structure of the rat endophilin A1 dimer determined crystallographically is maintained under predominantly vesiculating conditions. Spin-labeled side chains on the concave surface of the BAR domain do not penetrate into the acyl chain interior, indicating that the BAR domain interacts only peripherally with the surface of a curved bilayer. Using a combination of EPR data and computational refinement, we determined the structure of residues 63-86, a region that is disordered in the crystal structure of rat endophilin A1. Upon membrane binding, residues 63-75 in each subunit of the endophilin dimer form a slightly tilted, amphipathic alpha-helix that directly interacts with the membrane. In their predominant conformation, these helices are located orthogonal to the long axis of the BAR domain. In this conformation, the amphipathic helices are positioned to act as molecular wedges that induce membrane curvature along the concave surface of the BAR domain.

| S-EPMC2888429 | biostudies-literature

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