Membrane Fluctuations Destabilize Clathrin Protein Lattice Order

Cordella, Nicholas; Lampo, Thomas J.; Mehraeen, Shafigh; Spakowitz, Andrew J.

doi:10.1016/j.bpj.2013.11.4505

Cited by 14 publications

(14 citation statements)

References 85 publications

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“…The magnitude of changes in membrane properties caused by mycolactone could, in principle, influence the activity of membrane-embedded proteins [ 49 ]. Previous studies have addressed how changes in membrane elastic properties can affect glucose transporters [ 50 ], the stability of voltage sensor segments [ 51 ], mechano-sensitive channels of large conductance [ 52 ], and clathrin protein ordering [ 53 ]. However, the most likely connection between membrane association and Sec61 inhibition is that trafficking to the endoplasmic reticulum could facilitate mycolactone binding to the Sec61 translocon.…”

Section: Discussionmentioning

confidence: 99%

Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans

et al. 2018

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Mycolactone is the exotoxin produced by Mycobacterium ulcerans and is the virulence factor behind the neglected tropical disease Buruli ulcer. The toxin has a broad spectrum of biological effects within the host organism, stemming from its interaction with at least two molecular targets and the inhibition of protein uptake into the endoplasmic reticulum. Although it has been shown that the toxin can passively permeate into host cells, it is clearly lipophilic. Association with lipid carriers would have substantial implications for the toxin’s distribution within a host organism, delivery to cellular targets, diagnostic susceptibility, and mechanisms of pathogenicity. Yet the toxin’s interactions with, and distribution in, lipids are unknown. Herein we have used coarse-grained molecular dynamics simulations, guided by all-atom simulations, to study the interaction of mycolactone with pure and mixed lipid membranes. Using established techniques, we calculated the toxin’s preferential localization, membrane translocation, and impact on membrane physical and dynamical properties. The computed water-octanol partition coefficient indicates that mycolactone prefers to be in an organic phase rather than in an aqueous environment. Our results show that in a solvated membrane environment the exotoxin mainly localizes in the water-membrane interface, with a preference for the glycerol moiety of lipids, consistent with the reported studies that found it in lipid extracts of the cell. The calculated association constant to the model membrane is similar to the reported association constant for Wiskott-Aldrich syndrome protein. Mycolactone is shown to modify the physical properties of membranes, lowering the transition temperature, compressibility modulus, and critical line tension at which pores can be stabilized. It also shows a tendency to behave as a linactant, a molecule that localizes at the boundary between different fluid lipid domains in membranes and promotes inter-mixing of domains. This property has implications for the toxin’s cellular access, T-cell immunosuppression, and therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans

et al. 2018

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“…Previous simulations on budding of nanoscale particles led to important insights but did not consider the effect of GPs ( [24][25][26][27][28][29][30][31]), although budding directed by GP adsorption or capsid assembly have been the subject of continuum theoretical modeling [32][33][34]. The formation of clathrin cages during vesicle secretion, a process which bears similarities to viral budding, has also been the subject of modeling studies [35][36][37][38]. Most closely related to our work are previous simulations on the assembly and budding of 12-subunit capsids, which found that membrane adsorption can lower entropic barriers to assembly [39,40] and that membrane microdomains can facilitate assembly and budding [41].…”

Section: Introductionmentioning

confidence: 99%

Why Enveloped Viruses Need Cores—The Contribution of a Nucleocapsid Core to Viral Budding

Lázaro

Mukhopadhyay

Hagan

2018

Biophysical Journal

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During the lifecycle of many enveloped viruses, a nucleocapsid core buds through the cell membrane to acquire an outer envelope of lipid membrane and viral glycoproteins. However, the presence of a nucleocapsid core is not required for assembly of infectious particles. To determine the role of the nucleocapsid core, we develop a coarse-grained computational model with which we investigate budding dynamics as a function of glycoprotein and nucleocapsid interactions, as well as budding in the absence of a nucleocapsid. We find that there is a transition between glycoprotein-directed budding and nucleocapsid-directed budding that occurs above a threshold strength of nucleocapsid interactions. The simulations predict that glycoprotein-directed budding leads to significantly increased size polydispersity and particle polymorphism. This polydispersity can be explained by a theoretical model accounting for the competition between bending energy of the membrane and the glycoprotein shell. The simulations also show that the geometry of a budding particle leads to a barrier to subunit diffusion, which can result in a stalled, partially budded state. We present a phase diagram for this and other morphologies of budded particles. Comparison of these structures against experiments could establish bounds on whether budding is directed by glycoprotein or nucleocapsid interactions. Although our model is motivated by alphaviruses, we discuss implications of our results for other enveloped viruses.

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“…These experimental studies are complimented by the modeling work by Walani et al which suggests that an increase in tension should lead to smaller clathrin coat in order to match experimentally observed shapes observed in mammalian and yeast cells 17 . In addition, stochastic models have given fundamental insights into clathrin self-assembly 18,19 and dynamic rearrangements in clathrin lattices 20–22 . In particular, curvature generation by indentation has been shown to promote solid to fluid phase transition in a planar clathrin lattice 21 .…”

Section: Introductionmentioning

confidence: 99%

Clathrin polymerization exhibits high mechano-geometric sensitivity

et al. 2017

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How tension modulates cellular transport has become a topic of interest in the recent past. The effect of tension on clathrin assembly and vesicle growth continues to remain less understood. Here, we use the classical Helfrich theory to predict the energetic cost clathrin is required to pay to remodel membrane at different stages of vesicle formation. Our study reveals that this energetic cost is highly sensitive to not only the tension in the membrane but to the instantaneous geometry of the membrane during the shape evolution. Our study predicts a sharp reduction in clathrin coat size in the intermediate tension regime (0.01 − 0.1 mN/m). Remarkably, the natural propensity of the membrane to undergo bending beyond the Ω shape causes a significant decrease in the energy needed from clathrin to drive vesicle growth. Our studies in mammalian cells confirm a reduction in clathrin coat size in increased tension environment. In addition, our findings suggest that the two apparently distinct clathrin assembly modes, namely coated pits and coated plaques, observed in experimental investigations might be a consequence of varied tensions in the plasma membrane. Overall, the mechano-geometric sensitivity revealed in this study might also be at play during the polymerization of other membrane remodeling proteins.

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Membrane Fluctuations Destabilize Clathrin Protein Lattice Order

Cited by 14 publications

References 85 publications

Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans

Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans

Why Enveloped Viruses Need Cores—The Contribution of a Nucleocapsid Core to Viral Budding

Clathrin polymerization exhibits high mechano-geometric sensitivity

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