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.
Highlights
Nature uses dynamic molecular platforms for the recruitment of weakly associating proteins into higher-order assemblies to achieve spatiotemporal control of signal transduction
Stupp and coworkers reported the development of sulfated glycopeptide nanostructures as highly active, adaptive scaffolds for the binding of various growth factor proteins, efficiently promoting bone regeneration in the spine[15]. Another noticeable example is the work of Brunsveld and coworkers, who explored the use of supramolecular polymers consisting of amphiphilic discotics to control the assembly of fluorescent proteins, using Förster resonance energy transfer (FRET) to study the dynamic exchange of protein functionalized monomers between different polymer chains[16,17]
Our finding that supramolecular interactions between the relatively small BTAs are sufficient to coordinate the assembly of protein complexes via DNA hybridization is quite remarkable
Summary
Nature uses dynamic molecular platforms for the recruitment of weakly associating proteins into higher-order assemblies to achieve spatiotemporal control of signal transduction. Signaling pathways that govern processes such as cytoskeletal remodeling, proliferation, gene expression, and metabolic regulation all involve the transient formation of higher-order protein complexes These signal transduction cascades use specific scaffold proteins, membrane surfaces, or micro-phase-separated states as dynamic recruitment platforms to engage weakly associating proteins into higher-order assemblies[2,3,4]. Stupp and coworkers reported the development of sulfated glycopeptide nanostructures as highly active, adaptive scaffolds for the binding of various growth factor proteins, efficiently promoting bone regeneration in the spine[15] Another noticeable example is the work of Brunsveld and coworkers, who explored the use of supramolecular polymers consisting of amphiphilic discotics to control the assembly of fluorescent proteins, using Förster resonance energy transfer (FRET) to study the dynamic exchange of protein functionalized monomers between different polymer chains[16,17]. Our results establish supramolecular BTA polymers as a remarkably robust platform for DNA-mediated recruitment of proteins and demonstrate how the assembly of protein complexes along the supramolecular polymer allows efficient and dynamic control of protein activity
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