Catalytic peptide-based coacervates for enhanced function through structural organization and substrate specificity

Reis, David Q.P.; Pereira, Sara; Ramos, Ana P.; Pereira, Pedro M.; Morgado, Leonor; Calvário, Joana; Henriques, Adriano O.; Serrano, Mónica; Pina, Ana S.

http://hdl.handle.net/10362/178560

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Autores

Henriques, Adriano O.

Serrano, Mónica

Pina, Ana S.

Resumo(s)

Liquid-liquid phase separation (LLPS) in living cells provides innovative pathways for synthetic compartmentalized catalytic systems. While LLPS has been explored for enhancing enzyme catalysis, its potential application to catalytic peptides remains unexplored. Here, we demonstrate the use of coacervation, a key LLPS feature, to constrain the conformational flexibility of catalytic peptides, resulting in structured domains that enhance peptide catalysis. Using the flexible catalytic peptide P7 as a model, we induce reversible biomolecular coacervates with structured peptide domains proficient in hydrolyzing phosphate ester molecules and selectively sequestering phosphorylated proteins. Remarkably, these coacervate-based microreactors exhibit a 15,000-fold increase in catalytic efficiency compared to soluble peptides. Our findings highlight the potential of a single peptide to induce coacervate formation, selectively recruit substrates, and mediate catalysis, enabling a simple design for low-complexity, single peptide-based compartments with broad implications. Moreover, LLPS emerges as a fundamental mechanism in the evolution of chemical functions, effectively managing conformational heterogeneity in short peptides and providing valuable insights into the evolution of enzyme activity and catalysis in prebiotic chemistry.

Descrição

This work was partially supported by PPBI - Portuguese Platform of BioImaging (PPBI-POCI-01-0145-FEDER-022122) co-funded by national funds from OE - \u201COr\u00E7amento de Estado\u201D and by european funds from FEDER - \u201CFundo Europeu de Desenvolvimento Regional. La Caixa Junior Leader Fellowship (LCF/BQ/PI20/11760012) financed by\u201Dla Caixa\u201D Foundation (ID 100010434) and a Maratona da Sa\u00FAde award. The NMR spectrometers at CERMAX, ITQB-NOVA, Oeiras are funded by FCT through project AAC 01/SAICT/2016, while those from FCT-NOVA are part of the National NMR Network and are supported by FCT (ROTEIRO/0031/2013) cofounded by FEDER through COMPETE 2020, POCI, PORL and FCT through PIDDAC. Publisher Copyright: © The Author(s) 2024.