Controlling protein activity by dynamic recruitment on a supramolecular polymer platform

Abstract

Nature uses dynamic molecular platforms for the recruitment of weakly associating proteins into higher-order assemblies to achieve spatiotemporal control of signal transduction. Nanostructures that emulate this dynamic behavior require features such as plasticity, specificity and reversibility. Here we introduce a synthetic protein recruitment platform that combines the dynamics of supramolecular polymers with the programmability offered by DNA-mediated protein recruitment. Assembly of benzene-1,3,5-tricarboxamide (BTA) derivatives functionalized with a 10-nucleotide receptor strand into µm-long supramolecular BTA polymers is remarkably robust, even with high contents of DNA-functionalized BTA monomers and associated proteins. Specific recruitment of DNA-conjugated proteins on the supramolecular polymer results in a 1000-fold increase in protein complex formation, while at the same time enabling their rapid exchange along the BTA polymer. Our results establish supramolecular BTA polymers as a generic protein recruitment platform and demonstrate how assembly of protein complexes along the supramolecular polymer allows efficient and dynamic control of protein activity.

Self‐Healing Supramolecular Hydrogels for Tissue Engineering Applications

“…Recently, this method of self‐assembly has received increased attention, and has been combined with principles of DNA‐origami to enable precise control over the spatial distribution and recruitment of proteins in adaptive scaffolds. Most recently, self‐assembly of BTA monomers were used to form 1D supramolecular polymers that allow facile incorporation of various and DNA‐functionalized BTA monomers that enabled efficient and dynamic control of protein activity along the polymer . Functional BTAs have been incorporated into hydrogels for siRNA capture that represent a versatile platform for further development of various functionalized BTA polymers .…”

Dynamic modulation of proximity-induced enzyme activity using supramolecular polymers

“…[13][14][15] In addition, supramolecular polymers can be used as modular templates for the assembly of various biomolecules, including nanoparticles, 16,17 nucleic acids, 18,19 and proteins. [20][21][22][23] Recent work has revealed that intracellular signalling pathways heavily rely on the dynamic assembly of higher-order fibril-like aggregates that are structurally well-defined but open-ended and sometimes quasi-infinite. 24,25 As such, these assemblies function as platforms for the transient recruitment of signalling proteins that undergo proximity-induced activation, 26,27 and subsequently elicit immune or inflammatory responses, or apoptosis.…”

DNA-inspired oligomers: from oligophosphates to functional materials

“…5F). 34 The functional polymer was assembled from two monomers -1,3,5-benzenetricarboxamide (BTA) and the corresponding DNA conjugate, prepared via click chemistry from azide 25. These molecules share a BTA self-assembling motif, ensuring efficient integration of variable amounts of the conjugate (0-100 mol%) in the stacks of supramolecular polymers via triple hydrogen bonding, stacking and hydrophobic interactions.…”