Peptide-PARC: Programmable Coacervation of short peptides into Artificial Regulatory Compartments

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

Publication . Reis, David Q.P.; Pereira, Sara; Ramos, Ana P.; Pereira, Pedro M.; Morgado, Leonor; Calvário, Joana; Henriques, Adriano O.; Serrano, Mónica; Pina, Ana S.; Instituto de Tecnologia Química e Biológica António Xavier (ITQB); UCIBIO - Applied Molecular Biosciences Unit; Faculdade de Ciências e Tecnologia (FCT); Nature Portfolio

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.

2024-10-30Artigo científico

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Fundação para a Ciência e a Tecnologia

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CEEC IND4ed

Número da atribuição

2021.01283.CEECIND/CP1657/CT0004