Local environment in biomolecular condensates modulates enzymatic activity across length scales

Marcos Gil-Garcia, Ana I. Benítez-Mateos, Marcell Papp, Florence Stoffel, Chiara Morelli, Karl Normak, Katarzyna Makasewicz, Lenka Faltova, Francesca Paradisi and Paolo Arosio ()
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Marcos Gil-Garcia: ETH Zurich
Ana I. Benítez-Mateos: University of Bern
Marcell Papp: ETH Zurich
Florence Stoffel: ETH Zurich
Chiara Morelli: ETH Zurich
Karl Normak: ETH Zurich
Katarzyna Makasewicz: ETH Zurich
Lenka Faltova: ETH Zurich
Francesca Paradisi: University of Bern
Paolo Arosio: ETH Zurich

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract The mechanisms that underlie the regulation of enzymatic reactions by biomolecular condensates and how they scale with compartment size remain poorly understood. Here we use intrinsically disordered domains as building blocks to generate programmable enzymatic condensates of NADH-oxidase (NOX) with different sizes spanning from nanometers to microns. These disordered domains, derived from three distinct RNA-binding proteins, each possessing different net charge, result in the formation of condensates characterized by a comparable high local concentration of the enzyme yet within distinct environments. We show that only condensates with the highest recruitment of substrate and cofactor exhibit an increase in enzymatic activity. Notably, we observe an enhancement in enzymatic rate across a wide range of condensate sizes, from nanometers to microns, indicating that emergent properties of condensates can arise within assemblies as small as nanometers. Furthermore, we show a larger rate enhancement in smaller condensates. Our findings demonstrate the ability of condensates to modulate enzymatic reactions by creating distinct effective solvent environments compared to the surrounding solution, with implications for the design of protein-based heterogeneous biocatalysts.

Date: 2024
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DOI: 10.1038/s41467-024-47435-w

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