Organizing membrane-curving proteins: the emerging dynamical picture

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Highlights

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    Membrane reshaping in the cell, such as during trafficking, endocytosis, division and other phenomena, is highly dynamic and typically involves a multitude of components. Coarse-grained computer simulations complement experimental measurements by elucidating the molecular and dynamic aspects of these phenomena.

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    We review recent advances in coarse-grained modeling of lipids and membrane proteins, with emphasis on how they were used to study membrane deformations by proteins in the course of endocytosis.

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    In recent years, coarse-grained simulations have shed light on an important emerging aspect of protein-membrane interactions: while proteins can affect membrane shape both locally and globally, employing a variety of different mechanisms, membranes themselves can direct protein assembly, by modulating local curvature, surface tension, and other parameters.

Lipid membranes play key roles in cells, such as in trafficking, division, infection, remodeling of organelles, among others. The key step in all these processes is creating membrane curvature, typically under the control of many anchored, adhered or included proteins. However, it has become clear that the membrane itself can mediate the interactions among proteins to produce highly ordered assemblies. Computer simulations are ideally suited to investigate protein organization and the dynamics of membrane remodeling at near-micron scales, something that is extremely challenging to tackle experimentally. We review recent computational efforts in modeling protein-caused membrane deformation mechanisms, specifically focusing on coarse-grained simulations. We highlight work that exposed the membrane-mediated ordering of proteins into lines, meshwork, spirals and other assemblies, in what seems to be a very generic mechanism driven by a combination of short and long-ranged forces. Modulating the mechanical properties of membranes is an underexplored signaling mechanism in various processes deserving of more attention in the near future.

Section snippets

Dynamics of cell membranes at multiple scales: the need for coarse-grained computer simulations

The cell membrane is the first stop en route into the cell. While integral membrane proteins, such as signaling receptors, often control the trafficking of cargo in and out of the cell, lipid membranes play significant roles in this process. The most common way of entering the cell is via endocytosis, in which a small portion of the membrane curves and eventually breaks off, handing over the engulfed cargo down the path of intracellular trafficking. Membrane curvature is essential for many

General mechanisms of membrane bending by BAR domains and other proteins

Many proteins regulate membrane curvature in the cell. The basis of their interactions typically involves inducing a local asymmetry in the lipid bilayer either by virtue of their shape, local clustering, inclusion into the bilayer, active force, or by a combination of multiple effects [1]. Many proteins bind peripherally to interact with a membrane's shape. Typically they are themselves intrinsically curved or they form curved multi-protein assemblies when bound to the surface. Examples

Bending membranes by proteins: insights from CG simulations

Many CG lipid and protein models with varying degree of coarseness have been designed in the recent years to study membrane bending by proteins (Figure 1a,b). The higher-resolution CG models, such as MARTINI [10], retain much of the sub-molecular information and are therefore well suited for questions where the chemical specificity of components is important (Figure 1a). For instance, MARTINI MD simulations have shown how the embedded voltage sensor Kv [11] or small peptides [12] couple with

Membranes mediate the formation of highly ordered protein assemblies

Simulations summarized in the previous section demonstrated that protein-bilayer interactions can give rise to local and global membrane deformations. However, the reverse process — the effect of membrane curvature on protein interactions — is equally important in understanding membrane-remodeling phenomena. It is especially important in the context of BAR proteins, which, according to experimental measurements, do not induce global curvature when sparsely bound to the membrane; rather, they most

Future outlook

We expect CG simulation to tackle several more complex questions in the near future. First, every membrane-remodeling phenomenon involves multiple types of proteins and their correct and timely assembly. It will be interesting to use CG models to simulate multiple BAR proteins, and BAR proteins interacting with other types of proteins, such as epsins and clathrin, in the same system. These simulations will help in resolving the controversial issue of the temporal order of recruitment and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

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  • •• of outstanding interest

Acknowledgements

MS and GAV acknowledge their research reported in this publication as being supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number R01-GM063796. The PB group belongs to the CNRS consortium CellTiss; to Labex CelTisPhyBio (ANR-11-LABX0038) and to Paris Sciences et Lettres (ANR-10-IDEX-0001-02). MS is a Junior Fellow of the Simons Society of Fellows.

References (52)

  • M.G. Saunders et al.

    Coarse-graining methods for computational biology

    Annu Rev Biophys

    (2013)
  • B. Qualmann et al.

    Let's go bananas: revisiting the endocytic BAR code

    EMBO J

    (2011)
  • B. Sorre et al.

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

    Proc Natl Acad Sci U S A

    (2012)
  • Z. Shi et al.

    Membrane tension and peripheral protein density mediate membrane shape transitions

    Nat Commun

    (2015)
  • M. Simunovic et al.

    How curvature-generating proteins build scaffolds on membrane nanotubes

    Proc Natl Acad Sci U S A

    (2016)
  • M. Simunovic et al.

    Friction mediates scission of tubular membranes scaffolded by BAR proteins

    Cell

    (2017)
  • S.J. Marrink et al.

    Perspective on the Martini model

    Chem Soc Rev

    (2013)
  • P.J. Bond et al.

    Bilayer deformation by the Kv channel voltage sensor domain revealed by self-assembly simulations

    Proc Natl Acad Sci U S A

    (2007)
  • M. Fuhrmans et al.

    Molecular view of the role of fusion peptides in promoting positive membrane curvature

    J Am Chem Soc

    (2012)
  • A.R. Braun et al.

    alpha-Synuclein's uniquely long amphipathic helix enhances its membrane binding and remodeling capacity

    J Membr Biol

    (2017)
  • A.R. Braun et al.

    alpha-Synuclein-induced membrane remodeling is driven by binding affinity, partition depth, and interleaflet order asymmetry

    J Am Chem Soc

    (2014)
  • A. Srivastava et al.

    A hybrid approach for highly coarse-grained lipid bilayer models

    J Chem Theory Comput

    (2013)
  • A. Saric et al.

    Self-assembly of nanoparticles adsorbed on fluid and elastic membranes

    Soft Matter

    (2013)
  • B.J. Reynwar et al.

    Membrane-mediated interactions between circular particles in the strongly curved regime

    Soft Matter

    (2011)
  • R. Vacha et al.

    Receptor-mediated endocytosis of nanoparticles of various shapes

    Nano Lett

    (2011)
  • V. Schubertova et al.

    Design of multivalent inhibitors for preventing cellular uptake

    Sci Rep

    (2017)

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