ATPase activity profiling of three human DExD/H-box RNA helicases

Human DExD/H-box RNA helicases are ubiquitous molecular motors that unwind and rearrange RNA secondary structures in an ATP-dependent manner. These enzymes play essential roles in nearly all aspects of RNA metabolism. While their biological functions are well-characterized, the kinetic mechanisms re...

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Main Authors: Fengling Li, U Hang Chan, Julia Garcia Perez, Hong Zeng, Irene Chau, Yanjun Li, Almagul Seitova, Levon Halabelian
Format: Article
Language:English
Published: Elsevier 2025-04-01
Series:SLAS Discovery
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Online Access:http://www.sciencedirect.com/science/article/pii/S247255522500022X
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Summary:Human DExD/H-box RNA helicases are ubiquitous molecular motors that unwind and rearrange RNA secondary structures in an ATP-dependent manner. These enzymes play essential roles in nearly all aspects of RNA metabolism. While their biological functions are well-characterized, the kinetic mechanisms remain relatively understudied in vitro. In this study, we describe the development and optimization of a bioluminescence-based assay to characterize the ATPase activity of three human RNA helicases: MDA5, LGP2, and DDX1. The assays were conducted using annealed 24-mer ds-RNA (blunt-ended double-stranded RNA) or double-stranded RNA with a 25-nt 3ʹ overhang (partial ds-RNA). These findings establish a robust and high-throughput in vitro assay suitable for a 384-well format, enabling the discovery and characterization of inhibitors targeting MDA5, LGP2, and DDX1. This work provides a valuable resource for advancing our understanding of these helicases and their therapeutic potential in Alzheimer's disease.
ISSN:2472-5552