Dépôt numérique

Ancestral sequence reconstruction dissects structural and functional differences among eosinophil ribonucleases

Tran, Thi Thanh Quynh; Narayanan, Chitra; Loes, Andrea N; Click, Timothy H; Pham, Ngoc Thu Hang; Létourneau, Myriam; Harms, Michael J; Calmettes, Charles ORCID logoORCID: https://orcid.org/0000-0002-2542-4382; Agarwal, Pratul K et Doucet, Nicolas ORCID logoORCID: https://orcid.org/0000-0002-1952-9380 (2024). Ancestral sequence reconstruction dissects structural and functional differences among eosinophil ribonucleases Journal of Biological Chemistry , nº 107280. DOI: 10.1016/j.jbc.2024.107280. (Sous Presse)

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Evolutionarily conserved structural folds can give rise to diverse biological functions, yet predicting atomic-scale interactions that contribute to the emergence of novel activities within such folds remains challenging. Pancreatic-type ribonucleases illustrate this complexity, sharing a core structure that has evolved to accommodate varied functions. In this study, we used ancestral sequence reconstruction to probe evolutionary and molecular determinants that distinguish biological activities within eosinophil members of the RNase 2/3 subfamily. Our investigation unveils functional, structural, and dynamical behaviors that differentiate the evolved ancestor AncRNase from its contemporary eosinophil RNase orthologs. Leveraging the potential of ancestral reconstruction for protein engineering, we used AncRNase predictions to design a minimal 4-residue variant that transforms human RNase 2 into a chimeric enzyme endowed with the antimicrobial and cytotoxic activities of RNase 3 members. This work provides unique insights into mutational and evolutionary pathways governing structure, function, and conformational states within the eosinophil RNase subfamily, offering potential for targeted modulation of RNase-associated functions.

Type de document: Article
Mots-clés libres: RNase 2; RNase 3; X-ray crystallography; Ancestral RNase; Ancestral sequence reconstruction; Chimeragenesis; Eosinophil; Eosinophil cationic protein; Eosinophil-derived neurotoxin; Molecular dynamics; Protein evolution; Structural biology
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 29 avr. 2024 15:41
Dernière modification: 29 avr. 2024 15:41
URI: https://espace.inrs.ca/id/eprint/15631

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