Mechanisms Shaping Cell Membranes

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Mechanisms Shaping Cell Membranes Available online at www.sciencedirect.com ScienceDirect Mechanisms shaping cell membranes 1 2,3 4 5 Michael M Kozlov , Felix Campelo , Nicole Liska , Leonid V Chernomordik , 6 4 Siewert J Marrink and Harvey T McMahon Membranes of intracellular organelles are characterized by three-way junctions into an elaborate three-dimensional large curvatures with radii of the order of 10–30 nm. While, network, and micron wide sheets with a thickness similar to generally, membrane curvature can be a consequence of any that of the tubes [1,2]. The sheets can be stacked by asymmetry between the membrane monolayers, generation of peculiar helicoidal membrane connections [3], can have large curvatures requires the action of mechanisms based on fenestrations [4] and their rims are connected to the tubes. specialized proteins. Here we discuss the three most relevant The 10–20 nm thick cisternae of the Golgi Complex (GC) classes of such mechanisms with emphasis on the physical are stacked, strongly fenestrated, and undergo constituent requirements for proteins to be effective in generation of material exchange by fusion and fission with spherical membrane curvature. We provide new quantitative estimates of vesicles and pleiomorphic traffic intermediates [5,6]. membrane bending by shallow hydrophobic insertions and The inner membranes of mitochondria are compartmen- compare the efficiency of the insertion mechanism with those talized into numerous cristae, the thin sheet-like structures of the protein scaffolding and crowding mechanisms. similar in their dimensions to the ER sheets and GC Addresses cisternae [7,8]. A common feature of all these structures 1 Department of Physiology and Pharmacology, Sackler Faculty of is the large membrane curvature seen in their cross-sec- Medicine, Tel Aviv University, 69978 Tel Aviv, Israel tions. The radii of these curvatures, varying in the range of 2 Cell and Developmental Biology Programme, Centre for Genomic 10–30 nm, are only a few times larger compared to the 4– Regulation (CRG), 08003 Barcelona, Spain 3 5 nm thicknesses of the membranes. Similarly large cur- Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain 4 MRC Laboratory of Molecular Biology, Francis Crick Avenue, vatures characterize also other intracellular membranes Cambridge Biomedical Campus, Cambridge CB2 0QH, UK such as endocytic vesicles [9,10 ,11] and caveolae [12,13]. 5 Section on Membrane Biology, Program of Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, A question arises whether generation of large membrane National Institutes of Health, Bethesda, MD 20892, United States 6 curvatures and the related intricate shapes of intracellular Groningen Biomolecular Sciences and Biotechnology Institute and Zernike Institute for Advanced Materials, University of Groningen, compartments is an easy task for cells, which can be Nijenborgh 7, 9747 AG Groningen, The Netherlands completed using nonspecific mechanisms based on ther- mal undulations of the membrane surface, or whether Corresponding authors: Kozlov, Michael M ([email protected]) and cells must utilize special molecular mechanisms consum- McMahon, Harvey T ([email protected]) ing energy and employing specialized proteins. The answer to this question can be reduced to the physical Current Opinion in Cell Biology 2014, 29:53–60 and, more specifically, mechanical properties of mem- Cell organelles This review comes from a themed issue on branes. From a physical point of view, membranes can be Edited by William A Prinz and David K Banfield defined as nano-films consisting of a mixture of lipids and proteins. The structural basis of any biological membrane is a few nanometres thick lipid bilayer, which forms by self-organization of amphipathic molecules of phospho- 0955-0674/$ – see front matter, # 2014 Elsevier Ltd. All rights reserved. lipids within aqueous solutions [14]. Proteins bind lipid http://dx.doi.org/10.1016/j.ceb.2014.03.006 bilayers by inserting their hydrophobic domains into the bilayer interior and/or through attraction of their hydro- philic domains to the bilayer surface mediated by such Introduction physical forces as electrostatic, Van-der-Waals or hydro- gen bonding forces [15,16]. Biological membranes serve as envelopes around cells and intracellular compartments and, are hence crucial for pro- viding insulation of intracellular life from the environment There are two competing physical properties of lipid and enabling the complexity of intracellular processes. bilayers, whose interplay enables the ability of the mem- branes to serve as universal biological wrappers and deter- Most intracellular membranes have highly complex shapes mines the shapes of the resulting membrane envelopes. characterized by a large ratio between the area and the enclosed volume. A biological reason for this is the neces- On one hand, a homogeneous lipid bilayer formed by sity to facilitate or accelerate the molecular exchange individual lipids prefers to remain flat and is resistant to between the luminal volume bounded by the membrane any deviation from this shape by bending. The tendency to and the cytosol. Peripheral endoplasmic reticulum (ER) flatness is dictated by the symmetry of its monolayers. The consists of 30–50 nm thick tubules interconnected by resistance to bending is determined by the intra-monolayer www.sciencedirect.com Current Opinion in Cell Biology 2014, 29:53–60 54 Cell organelles interactions between the lipid molecules. In spite of a All these system must be able to develop forces sufficient common intuitive feeling that a 4 nm thick film consisting for generation of the relevant membrane curvatures with of soft biological matter should be absolutely flexible, a radii of about r = 10 nm. A required force f can be typical lipid bilayer is characterized by bending rigidity of estimated by dividing the membrane bending rigidity k about k = 20 kBT (where kBT 0.6 kcal/mol is a product of by r, which gives f = k/r 10 pN. A characteristic the Boltzmann constant and the absolute temperature). maximal force, which can be produced by one polymer- This rigidity is an order of magnitude larger than a charac- izing actin filament or one molecular motor is of the order teristic energy of about 1 kBT provided by thermal fluctu- of 1 pN [23,24]. Hence, ensembles of several molecular ations, which means that the latter cannot determine motors working in concert, or bundles keeping together membrane shapes. tens of polymerizing actin filaments must have enough power to provide the required curvatures. On the other hand, any bilayer tends to be continuous, resisting all kinds of ruptures and structural defects and, At the same time, a crucial question arises about the particularly, it avoids having edges [17]. In order to get rid specific means by which these forces have to be trans- of its external edge, any initially flat bilayer has to adopt a mitted to the membrane. The forces would be ineffec- closed shape, which is unavoidably accompanied by the tive if applied tangentially to the membrane surface. bilayer bending [18]. Hence, the membrane bending The reason for this is that protein anchors connecting rigidity and the tendency to prevent edge formation the polymerizing filament tips or the molecular motors compete. This competition results in any bilayer frag- to the membrane must be freely movable along the ment larger than 200 nm in diameter adopting a closed membrane plane due to the two-dimensional membrane spherical shape whose bending energy is about fluidity. As a result, in the tangential direction only 8pk = 500kBT 300 kcal/mol (which is independent of transient and weak viscous forces [25–27] but not the the sphere radius) [18]. long lasting elastic forces needed for the generation of stable curvature can be transmitted. To be effective, In conclusion, according to their basic physical properties, the forces have to be directed normally to the mem- homogeneous and symmetric lipid bilayers tend to adopt brane plane and applied to limited spots of the mem- shapes of closed spheres. Deviations of the bilayer shape brane area. At the same time the bulk of the membrane from the spherical one require either changes of the has to be under lateral tension counteracting the applied bilayer structural properties making it asymmetric or force. Such setup is realized, for example, in artificial applications of forces to the bilayer surface providing systems where membrane tethers of large curvatures are energies in the range of tens to hundreds of kcal/mol, pulled out of stressed giant vesicles by localized force depending on the extent of deformation. The membrane application through beads attached to the membrane asymmetry can be achieved by having different lipid surface (see e.g. [28 ]). In vivo, actin filament bundles compositions and/or different amounts of lipid molecules polymerizing against tensed plasma membranes must in the two monolayers [19]. Alternatively, asymmetry can be the major driving force of filopodia formation [29], be produced by asymmetric protein binding to the two while molecular motors accumulating at the tips of membrane sides. The forces acting on intracellular mem- microtubules and anchored in membranes must be able branes and deforming them can be produced only by to drive intracellular membrane tube formation (see for proteins or protein machines. review [30]). By analogy to membrane remodelling by fusion, which is Importantly, membrane tubes generated by the pulling or known for different fusion events to be driven by unre- pushing force application are persistently stretched and, lated proteins [20–22], it is conceivable that a cell therefore, the tubule axes must appear as straight lines. employs various molecular mechanisms for generation While this is true for filopodia under normal conditions of membrane curvatures and shapes of different subcel- [31], the tubules of ER look loose, their axes being bent lular compartments. Below we list and discuss some of [1,2]. It is conceivable that the pulling mechanisms may these mechanisms driven directly by proteins.
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