Significance of Receptor Mobility in Multivalent Binding on Lipid Membranes

Morzy, Diana; Bastings, Maartje M. C.

doi:10.1002/anie.202114167

Cited by 22 publications

(27 citation statements)

References 113 publications

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“…A low spatial tolerance decreases the conformational and combinatorial entropy penalties. 33 On the contrary, the higher conformational possibilities given by the linkers increases the entropic penalty of binding. The third effect may derive from a combination of the previous two, indicating that the observed average effect comes from a mixture of specific and nonspecific activation stimuli.…”

Section: Resultsmentioning

confidence: 99%

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Spatially Controlled Activation of Toll-like Receptor 9 with DNA-Based Nanomaterials

et al. 2022

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First evidence of geometrical patterns and defined distances of biomolecules as fundamental parameters to regulate receptor binding and cell signaling have emerged recently. Here, we demonstrate the importance of controlled nanospacing of immunostimulatory agents for the activation of immune cells by exploiting DNA-based nanomaterials and pre-existing crystallography data. We created DNA origami nanoparticles that present CpG-motifs in rationally designed spatial patterns to activate Toll-like Receptor 9 in RAW 264.7 macrophages. We demonstrated that stronger immune activation is achieved when active molecules are positioned at the distance of 7 nm, matching the active dimer structure of the receptor. Moreover, we show how the introduction of linkers between particle and ligand can influence the spatial tolerance of binding. These findings are fundamental for a fine-tuned manipulation of the immune system, considering the importance of spatially controlled presentation of therapeutics to increase efficacy and specificity of immune-modulating nanomaterials where multivalent binding is involved.

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Section: Resultsmentioning

confidence: 99%

“…It has been shown that reduced flexibility confers an advantage for the thermodynamics of ligand binding. A low spatial tolerance decreases the conformational and combinatorial entropy penalties . On the contrary, the higher conformational possibilities given by the linkers increases the entropic penalty of binding.…”

Section: Resultsmentioning

confidence: 99%

Spatially Controlled Activation of Toll-like Receptor 9 with DNA-Based Nanomaterials

et al. 2022

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“…56,57 Local high concentrations can temporarily be locked in place through changes in surrounding lipid dynamics. 20,49,58 From the receptor side, the boundary conditions for MPR and more general superselective multivalent interactions can be easily reached. As many natural ligands are present on precisely organized scaffolds, as in the case of viruses and geometric toxin complexes, 2,59 MPR is likely to be omnipresent in molecular biology.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…19 T h i s c o n t e n t i s Within a functional interaction complex in nature, the numbers of ligands and receptors are often low-to-moderate and their position in space can be (temporally) controlled. 20 Spatial organization of ligands is typically observed in pathogens (viruses), and our immune system is highly developed to recognize such patterns. 21 In microbiology, a classical welldefined system is seen in the multivalent interaction between the bacterial phages and their target receptor used in phage display.…”

Section: ■ Introductionmentioning

confidence: 99%

Multivalent Pattern Recognition through Control of Nano-Spacing in Low-Valency Super-Selective Materials

et al. 2022

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Super-selective multivalent ligand–receptor interactions display a signature step-like onset in binding when meeting a characteristic density of target receptors. Materials engineered for super-selective binding generally display a high number of flexible ligands to enhance the systems’ avidity. In many biological processes, however, ligands are present in moderate copy numbers and arranged in spatio-temporal patterns. In this low-valency regime, the rigidity of the ligand-presenting architecture plays a critical role in the selectivity of the multivalent complex through decrease of the entropic penalty of binding. Exploiting the precision in spatial design inherent to the DNA nanotechnology, we engineered a library of rigid architectures to explore how valency, affinity, and nano-spacing control the presence of super-selectivity in multivalent binding. A micromolar monovalent affinity was required for super-selective binding to be observed within low-valency systems, and the transition point for stable interactions was measured at hexavalent ligand presentation, setting the limits of the low-valency regime. Super-selective binding was observed for all hexavalent architectures, and, more strikingly, the ligand pattern determined the selectivity onset. Hereby, we demonstrate for the first time that nano-control of geometric patterns can be used to discriminate between receptor densities in a super-selective manner. Materials that were indistinguishable in their molecular composition and ligand valency bound with various efficacies on surfaces with constant receptor densities. We define this new phenomenon in super-selective binding as multivalent pattern recognition.

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“…The trends in binding efficacy observed across RGD scaffolds in function of α 5 β 1 in extended conformation can be explained as a trade-off in terms of the following: (i) a match of inter-receptor spacing to ligand presentation, (ii) number and density of integrins within a cluster [ 10 ] (iii) local cluster topography due to thickness of glycocalyx [ 58 ] (iv) potential binding sites per surface area probed (v) entropic penalty vs. enthalpic gain in scaffold binding through relatively rigid ligand presentation [ 59 , 60 ]. To elaborate on the complexity in the interpretation of the binding trends observed in terms of trade-off between glycocalyx thickness and enthalpy-entropy compensation, a thicker glycocalyx increases integrin-mediated cell adhesion by entrapment in an activated state once extended from the cell surface [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Selective Integrin α5β1 Targeting through Spatially Constrained Multivalent DNA-Based Nanoparticles

et al. 2022

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Targeting cells specifically based on receptor expression levels remains an area of active research to date. Selective binding of receptors cannot be achieved by increasing the individual binding strength, as this does not account for differing distributions of receptor density across healthy and diseased cells. Engaging receptors above a threshold concentration would be desirable in devising selective diagnostics. Integrins are prime target candidates as they are readily available on the cell surface and have been reported to be overexpressed in diseases. Insights into their spatial organization would therefore be advantageous to design selective targeting agents. Here, we investigated the effect of activation method on integrin α5β1 clustering by immunofluorescence and modeled the global neighbor distances with input from an immuno-staining assay and image processing of microscopy images. This data was used to engineer spatially-controlled DNA-scaffolded bivalent ligands, which we used to compare trends in spatial-selective binding observed across HUVEC, CHO and HeLa in resting versus activated conditions in confocal microscopy images. For HUVEC and CHO, the data demonstrated an improved selectivity and localisation of binding for smaller spacings ~7 nm and ~24 nm, in good agreement with the model. A deviation from the mode predictions for HeLa was observed, indicative of a clustered, instead of homogeneous, integrin organization. Our findings demonstrate how low-technology imaging methods can guide the design of spatially controlled ligands to selectively differentiate between cell type and integrin activation state.

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Significance of Receptor Mobility in Multivalent Binding on Lipid Membranes

Cited by 22 publications

References 113 publications

Spatially Controlled Activation of Toll-like Receptor 9 with DNA-Based Nanomaterials

Spatially Controlled Activation of Toll-like Receptor 9 with DNA-Based Nanomaterials

Multivalent Pattern Recognition through Control of Nano-Spacing in Low-Valency Super-Selective Materials

Selective Integrin α5β1 Targeting through Spatially Constrained Multivalent DNA-Based Nanoparticles

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