Crowding-induced membrane remodeling: Interplay of membrane tension, polymer density, architecture


      The plasma membrane hosts a wide range of biomolecules, mainly proteins and carbohydrates, that mediate cellular interactions with its environment. The crowding of such biomolecules regulates cellular morphologies and cellular trafficking. Recent discoveries have shown that the structure and density of cell surface polymers and hence the signaling machinery change with the state of the cell, especially in cancer progression. The alterations in membrane-attached glycocalyx and glycosylation of proteins and lipids are common features of cancer cells. The overexpression of glycocalyx polymers, such as mucin and hyaluronan, strongly correlates with cancer metastasis. Here, we present a mesoscale biophysics-based model that accounts for the shape regulation of membranes by crowding of membrane-attached biopolymer-glycocalyx and actin networks. Our computational model is based on the dynamically triangulated Monte Carlo model for membranes and coarse-grained representations of polymer chains. The model allows us to investigate the crowding-induced shape transformations in cell membranes in a tension- and graft polymer density-dependent manner. Our results show that the number of membrane protrusions and their shape depend on membrane tension, with higher membrane tension inducing more tubular protrusions than the vesicular shapes formed at low tension at high surface coverage of polymers. The shape transformations occur above the threshold density predicted by the polymer brush theory, but this threshold also depends on the membrane tension. Increasing the size of the polymer, either by changing the length or by adding side chains, is shown to increase the crowding-induced curvature. The effect of crowding is more prominent for flexible polymers than for semiflexible rigid polymers. We also present an extension of the model that incorporates properties of the actin-like filament networks and demonstrate how tubular structures can be generated by biopolymer crowding on the cytosolic side of cell membranes.
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        • Kirchhausen T.
        Bending membranes.
        Nat. Cell Biol. 2012; 14: 906-908
        • McMahon H.T.
        • Gallop J.L.
        Membrane curvature and mechanisms of dynamic cell membrane remodelling.
        Nature. 2005; 438: 590-596
        • Jarsch I.K.
        • Daste F.
        • Gallop J.L.
        Membrane curvature in cell biology: an integration of molecular mechanisms.
        J. Cell Biol. 2016; 214: 375-387
        • Stachowiak J.C.
        • Schmid E.M.
        • Hayden C.C.
        • et al.
        Membrane bending by protein–protein crowding.
        Nat. Cell Biol. 2012; 14: 944-949
        • Chen Z.
        • Atefi E.
        • Baumgart T.
        Membrane shape instability induced by protein crowding.
        Biophys. J. 2016; 111: 1823-1826
        • Snead W.T.
        • Hayden C.C.
        • Stachowiak J.C.
        • et al.
        Membrane fission by protein crowding.
        Proc. Natl. Acad. Sci. U S A. 2017; 112: E3258-E3267
        • Liese S.
        • Wenzel E.M.
        • Carlson A.
        • et al.
        Protein crowding mediates membrane remodeling in upstream ESCRT-induced formation of intraluminal vesicles.
        Proc. Natl. Acad. Sci. U S A. 2020; 117: 28614-28624
        • Kokolaki M.L.
        • Fauquier A.
        • Renner M.
        Molecular crowding and diffusion-capture in synapses.
        iScience. 2020; 23: 101382
        • Duncan A.L.
        • Reddy T.
        • Sansom M.S.P.
        • et al.
        Protein crowding and lipid complexity influence the nanoscale dynamic organization of ion channels in cell membranes.
        Sci. Rep. 2017; 7: 16647
        • Curry F.E.
        • Adamson R.H.
        Endothelial glycocalyx: permeability barrier and mechanosensor.
        Ann. Biomed. Eng. 2012; 40: 828-839
        • Weinbaum S.
        • Tarbell J.M.
        • Damiano E.R.
        The structure and function of the endothelial glycocalyx layer.
        Annu. Rev. Biomed. Eng. 2007; 9: 121-167
        • Möckl L.
        The emerging role of the mammalian glycocalyx in functional membrane organization and immune system regulation.
        Front. Cell Dev. Biol. 2020; 8
        • Hudak J.E.
        • Canham S.M.
        • Bertozzi C.R.
        Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion.
        Nat. Chem. Biol. 2014; 10: 69-75
        • Boligan K.F.
        • Mesa C.
        • Fernandez L.E.
        • von Gunten S.
        Cancer intelligence acquired (CIA): tumor glycosylation and sialylation codes dismantling antitumor defense.
        Cell. Mol. Life Sci. 2015; 72: 1231-1248
        • Hanahan D.
        • Weinberg R.A.
        The hallmarks of cancer.
        Cell. 2000; 100: 57-70
        • Hanahan D.
        • Weinberg R.
        Hallmarks of cancer: the next generation.
        Cell. 2011; 144: 646-674
        • Pinho S.S.
        • Reis C.A.
        Glycosylation in cancer: mechanisms and clinical implications.
        Nat. Rev. Cancer. 2015; 15: 540-555
        • Tarbell J.M.
        • Cancel L.M.
        The glycocalyx and its significance in human medicine.
        J. Intern. Med. 2016-07; 280: 97-113
        • Dennis J.W.
        • Nabi I.R.
        • Demetriou M.
        Metabolism, cell surface organization, and disease.
        Cell. 2009; 139: 1229-1241
        • Qazi H.
        • Shi Z.-D.
        • Tarbell J.M.
        • et al.
        Heparan sulfate proteoglycans mediate renal carcinoma metastasis.
        Int. J. Cancer. 2016-12-15; 139: 2791-2801
        • Moran H.
        • Cancel L.M.
        • Tarbell J.M.
        • et al.
        The cancer cell glycocalyx proteoglycan Glypican-1 mediates interstitial flow mechanotransduction to enhance cell migration and metastasis.
        Biorheology. 2019; 56: 151-161
        • Shurer C.R.
        • Kuo J.C.-H.
        • Paszek M.J.
        • et al.
        Physical principles of membrane shape regulation by the glycocalyx.
        Cell. 2019; 177: 1757-1770.e21
        • Stachowiak J.C.
        • Hayden C.C.
        • Sasaki D.Y.
        Steric confinement of proteins on lipid membranes can drive curvature and tubulation.
        Proc. Natl. Acad. Sci. U S A. 2010; 107: 7781-7786
        • Liese S.
        • Carlson A.
        Membrane shape remodeling by protein crowding.
        Biophys. J. 2021; 120: 2482-2489
        • Derganc J.
        • Čopič A.
        Membrane bending by protein crowding is affected by protein lateral confinement.
        Biochim. Biophys. Acta Biomembr. 2016; 1858: 1152-1159
        • Ho J.S.
        • Baumgartner A.
        Self-avoiding tethered membranes.
        Phys. Rev. Lett. 1989; 63: 1324
        • Ramakrishnan N.
        • Sunil Kumar P.B.
        • Ipsen J.H.
        Monte Carlo simulations of fluid vesicles with in-plane orientational ordering.
        Phys. Rev. E. 2010; 81: 041922
        • Kandy S.K.
        • Radhakrishnan R.
        Emergent membrane morphologies in relaxed and tense membranes in presence of reversible adhesive pinning interactions.
        Phys. Biol. 2019; 16: 066011
        • Helfrich W.
        Elastic properties of lipid bilayers: theory and possible experiments.
        Z. Naturforsch. C. 1973; 28: 693-703
        • Winterhalter M.
        • Helfrich W.
        Effect of surface charge on the curvature elasticity of membranes.
        J. Phys. Chem. 1988; 92: 6865-6867
        • Ramakrishnan N.
        • Sreeja K.K.
        • Radhakrishnan R.
        • et al.
        Excess area dependent scaling behavior of nano-sized membrane tethers.
        Phys. Biol. 2018; 15: 026002
        • Sens P.
        • Plastino J.
        Membrane tension and cytoskeleton organization in cell motility.
        J. Phys. Condens. Matter. 2015; 27: 273103
        • Blanchoin L.
        • Amann K.J.
        • Pollard T.D.
        • et al.
        Direct observation of dendritic actin filament networks nucleated by Arp2/3 complex and WASP/Scar proteins.
        Nature. 2000; 404: 1007-1011
        • Metropolis N.
        • Rosenbluth A.W.
        • Teller E.
        • et al.
        Equation of state calculations by fast computing machines.
        J. Chem. Phys. 1953; 21: 1087-1092
        • Breidenich M.
        • Netz R.R.
        • Lipowsky R.
        The shape of polymer-decorated membranes.
        Europhys. Lett. 2000; 49: 431-437
        • Lipowsky R.
        • Döbereiner H.-G.
        • Indrani V.
        • et al.
        Membrane curvature induced by polymers and colloids.
        Phys. Stat. Mech. Appl. 1998; 249: 536-543
        • Hiergeist C.
        • Lipowsky R.
        Elastic properties of polymer-decorated membranes.
        J. Phys. II France. 1996; 6: 1465-1481
        • Lipowsky R.
        Bending of membranes by anchored polymers.
        Europhys. Lett. 1995; 30: 197-202
        • Werner M.
        • Sommer J.-U.
        Polymer-decorated tethered membranes under good- and poor-solvent conditions.
        Eur. Phys. J. B. 2010; 31: 383-392
        • Auth T.
        • Gompper G.
        Self-avoiding linear and star polymers anchored to membranes.
        Phys. Rev. E. 2003; 68: 051801
        • Auth T.
        • Gompper G.
        Fluctuation spectrum of membranes with anchored linear and star polymers.
        Phys. Rev. E. 2005; 72: 031904
        • Wu H.
        • Shiba H.
        • Noguchi H.
        Mechanical properties and microdomain separation of fluid membranes with anchored polymers.
        Soft Matter. 2013; 9: 9907-9917
        • Kuo J.C.-H.
        • Gandhi J.G.
        • Paszek M.J.
        • et al.
        Physical biology of the cancer cell glycocalyx.
        Nat. Phys. 2018; 14: 658-669
        • Paturej J.
        • Sheiko S.S.
        • Rubinstein M.
        • et al.
        Molecular structure of bottlebrush polymers in melts.
        Sci. Adv. 2016; 2: e1601478
        • Subbotin A.
        • Saariaho M.
        • ten Brinke G.
        • et al.
        Elasticity of comb copolymer cylindrical brushes.
        Macromolecules. 2000; 33: 3447-3452
        • Turley E.A.
        • Wood D.K.
        • McCarthy J.B.
        Carcinoma cell hyaluronan as a “portable” cancerized prometastatic microenvironment.
        Cancer Res. 2016; 76: 2507-2512
        • Nyström B.
        • Kjøniksen A.-L.
        • García de la Torre J.
        • et al.
        Characterization of polyelectrolyte features in polysaccharide systems and mucin.
        Adv. Colloid Interface Sci. 2010; 158: 108-118
        • Daniel L.
        • Durbec P.
        • Figarella-Branger D.
        • et al.
        A nude mice model of human rhabdomyosarcoma lung metastases for evaluating the role of polysialic acids in the metastatic process.
        Oncogene. 2001; 20: 997-1004
        • Berezney J.P.
        • Saleh O.A.
        Electrostatic effects on the conformation and elasticity of hyaluronic acid, a moderately flexible polyelectrolyte.
        Macromolecules. 2017; 50: 1085-1089
        • Simon C.
        • Kusters R.
        • Sykes C.
        • et al.
        Actin dynamics drive cell-like membrane deformation.
        Nat. Phys. 2019; 15: 602-609
        • Ramakrishnan N.
        • Sunil Kumar P.
        • Radhakrishnan R.
        Mesoscale computational studies of membrane bilayer remodeling by curvature-inducing proteins.
        Phys. Rep. 2014; 543: 1-60
        • Sreeja K.K.
        • Sunil Kumar P.B.
        Lipid-protein interaction induced domains: kinetics and conformational changes in multicomponent vesicles.
        J. Chem. Phys. 2018; 148: 134703
        • Pfeifer C.R.
        • Alvey C.M.
        • Discher D.E.
        • et al.
        Genome variation across cancers scales with tissue stiffness – an invasion-mutation mechanism and implications for immune cell infiltration.
        Curr. Opin. Struct. Biol. 2017; 2: 103-114
        • Kang H.
        • Wu Q.
        • Deng X.
        • et al.
        Cancer cell glycocalyx and its significance in cancer progression.
        Int. J. Mol. Sci. 2018; 19: 2484
        • Northey J.J.
        • Przybyla L.
        • Weaver V.M.
        Tissue force programs cell fate and tumor aggression.
        Cancer Discov. 2017; 7: 1224-1237
        • Tourdot R.W.
        • Ramakrishnan N.
        • Radhakrishnan R.
        • et al.
        Application of a free-energy-landscape approach to study tension-dependent bilayer tubulation mediated by curvature-inducing proteins.
        Phys. Rev. E. 2015; 92: 042715