Ancestral sequence reconstruction dissects structural and functional differences among eosinophil ribonucleases

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 struc...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2024-05, Vol.300 (5), p.107280-107280, Article 107280
Main Authors: Tran, Thi Thanh Quynh, Narayanan, Chitra, Loes, Andrea N., Click, Timothy H., Pham, N.T.Hang, Létourneau, Myriam, Harms, Michael J., Calmettes, Charles, Agarwal, Pratul K., Doucet, Nicolas
Format: Article
Language:English
Subjects:
ancestral RNase
ancestral sequence reconstruction
chimeragenesis
eosinophil
eosinophil cationic protein
eosinophil-derived neurotoxin
molecular dynamics
protein evolution
RNase 2
RNase 3
structural biology
X-ray crystallography
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 ancestral ribonuclease (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.
ISSN:0021-9258
1083-351X
DOI:10.1016/j.jbc.2024.107280