Statistical Mechanics of an Elastically Pinned Membrane: Static Profile and Correlations

Janeš, Josip Augustin; Stumpf, Henning; Schmidt, Daniel R.; Seifert, Udo; Smith, Ana‐Sunčana

doi:10.1016/j.bpj.2018.12.003

Cited by 16 publications

(25 citation statements)

References 70 publications

(106 reference statements)

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“…The heterodimers were configured into orthogonal arrays with the periodicity of 200 nm in both x and y axis. This periodicity, which is twice larger than the average membrane correlation length (30), came to minimize any possible physical interaction between the neighboring dimers, and at the same time provide sufficient amount of ligands to stimulate NK cells.…”

Section: Device Design and Fabricationmentioning

confidence: 99%

Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells

Toledo

Saux

et al. 2020

Preprint

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The role of the spatial juxtaposition between activating and inhibitory receptors in cytotoxic lymphocytes has been strongly debated in the context of the inhibition of immune signaling. The challenge in addressing this problem was so far a lack of experimental tools which can simultaneously manipulate different signaling molecules. Here, we circumvent this challenge by introducing a nanoengineered multifunctional cell niche, in which activating and inhibitory ligands are positioned with molecular-scale variability and control, and applied it to elucidate the role of the spatial juxtaposition between ligands for NKG2D and KIR2DL1activating and inhibitory receptors in Natural Killer (NK) cellsin KIR2DL1-mediated inhibition of NKG2D signaling. We realized the niche by a nanopatterning of nanodots of different metals with molecular scale registry in one lithographic step, followed by a novel ternary functionalization of the fabricated bi-metallic pattern and its background to with three distinct biochemical moieties. We found, that within the probed range, the 40 nm gap between the activating and inhibitory ligands provided an optimal inhibition condition.Supported by theoretical modeling and simulations we interpret these findings as a consequence of the size and conformational flexibility of the ligands in their spatial interaction. Our findings provide an important insight onto the spatial mechanism of the inhibitory immune checkpoints, whose understanding is both fundamentally important, and essential for the rational design of future immunotherapies. Furthermore, our approach is highly versatile and paves the way to numerous complex molecular platforms aimed at revealing molecular mechanisms through which receptors integrate their signals.Cells communicate with their environment through a rich repertoire of receptors, whose signaling integration is mediated by the biochemistry of the cell-environment interface, as well as by diverse physical features, such as receptor size and spatial arrangement. In the immune synapsethe functional interface between lymphocytes and antigen-presenting cellsactivating, costimulatory, and inhibitory receptors coordinate their nanoscale clustering and arrangement to regulate lymphocyte immune activity(1, 2). For example, the spatial density and organization of T Cell Receptors (TCR) and their co-receptors CD3 within their nanoclusters regulate the phosphorylation of their complexes(3). Also, TCR and its linker for activation (LAT) concatenate during T cell activation, but form segregated clusters in resting T cells(4, 5). The inhibitory function of immune checkpoints that orchestrate the self-tolerance of the immune system, such as immunotherapeutic target PD-1 in T cells, or KIR2DL1 in NK cells, is associated with their nanoscale clustering and their segregation from activating and co-stimulatory receptors(6, 7), yet mechanism of these clustering and segregation, and their role in the activating-inhibitory signaling coordination, are still obscure. The systematic study of how the...

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Section: Device Design and Fabricationmentioning

confidence: 99%

Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells

Toledo

Saux

et al. 2020

Preprint

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“…1). Placing the origin of the coordinate system at the pinning site and into the minimum of the non-specific potential sets the form of the energy functional [43,45] as…”

Section: Equation Of Motionmentioning

confidence: 99%

“…External forces on the system are denoted by f (r, t), while the internal forces acting to minimize the Hamiltonian (eq. (1)) are given by the first variation [43] δH δu(r, t)…”

Section: Equation Of Motionmentioning

confidence: 99%

“…For ω = 0, the Green's function g f (r, ω) reduces to the static correlation function [43]. Consequently,…”

Section: A Free Membrane (λ = 0)mentioning

confidence: 99%

“…However, the presence of the pinning introduces a challenge, which is often circumvented by homogenising the effects of interactions with the scaffold [36,37]. Alternative approaches, where the local pinnings remain explicit, commonly involved simulations [38][39][40][41], while the theoretical modelling focused on the static properties of the membrane shape and fluctuations [37,42,43]. On the other hand, analytic treatments of the membrane-dynamics, even in the context of equilibrium, remained an open problem up to now.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Statistical Mechanics of an Elastically Pinned Membrane: Equilibrium Dynamics and Power Spectrum

Janeš

Schmidt

Blackwell

et al. 2019

Biophysical Journal

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In biological settings membranes typically interact locally with other membranes or the extracellular matrix in the exterior, as well as with internal cellular structures such as the cytoskeleton. Characterization of the dynamic properties of such interactions presents a difficult task. Significant progress has been achieved through simulations and experiments, yet analytical progress in modelling pinned membranes has been impeded by the complexity of governing equations. Here we circumvent these difficulties by calculating analytically the time-dependent Green's function of the operator governing the dynamics of an elastically pinned membrane in a hydrodynamic surrounding and subject to external forces. This enables us to calculate the equilibrium power spectral density for an overdamped membrane pinned by an elastic, permanently-attached spring subject to thermal excitations. By considering the effects of the finite experimental resolution on the measured spectra, we show that the elasticity of the pinning can be extracted from the experimentally measured spectrum. Membrane fluctuations can thus be used as a tool to probe mechanical properties of the underlying structures. Such a tool may be particularly relevant in the context of cell mechanics, where the elasticity of the membrane's attachment to the cytoskeleton could be measured.

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Biomechanics as driver of aggregation of tethers in adherent membranes

Kamal

Stumpf

et al. 2021

Soft Matter

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Statistical Mechanics of an Elastically Pinned Membrane: Static Profile and Correlations

Cited by 16 publications

References 70 publications

Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells

Molecular Scale Spatio-Chemical Control of the Activating-Inhibitory Signal Integration in NK Cells

Statistical Mechanics of an Elastically Pinned Membrane: Equilibrium Dynamics and Power Spectrum

Biomechanics as driver of aggregation of tethers in adherent membranes

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