Molecular Characterization of the DEAH-box Helicase DHX37 and Implication in RNA Processing and Human Disease

Authors

• JI Izu
• TT Ngo
• SJ Pleasure
• MR Wilson
• A Nath
• CM Bartley
• GC Mooneyham

Abstract

DEAH-box helicase, DHX37, is a multidomain protein that contains two RecA-like domains (RecA1 and RecA2), a helicase-associated domain (HA2), and an oligosaccharide-binding fold domain (OB). DHX37 is an ATP-binding RNA helicase crucial in maturation of the small ribosomal subunit in ribosome biogenesis and is required for the release of the U3 snoRNP from pre-ribosomal particles. The ATP-dependent 3'-5' RNA translocation stimulates ATPase activity and enhanced RNA binding. In the presence of clinically relevant DHX37 mutations, R490G and A898T, patients with juvenile dermatomyositis (JDM) and anti-MDA5 autoantibodies experience endothelial dysfunction. Evidence suggests types I and II IFN play a role in JDM, leading to Janus kinase (JAK) inhibitor being used to target the IFN pathway in these patients. Targeting the IFN pathway through inhibitor treatments may allow insight into reduction of disease activity in JDM and anti-MDA4 positive patients. Post-treatment assessment indicated down-regulation of symptoms associated with phenotype of MDA5 and functional impact of these mutations. Initial molecular characterization experiments analyzed wild-type DHX37 for the functionality of ATPase activity through kcat determination (the hydrolysis of ATP to ADP per time unit by DHX37, represented by per second units). The biochemical characterization of the A898T mutation indicated a more modest effect on any conformational changes than the R490G mutation. Additionally, the clinically associated DHX37 missense mutants display a robust molecular defect in comparison to wild-type DHX37 and indicate the inactivation of catalytic ATPase function.

Scientific Focus Area: Molecular Biology and Biochemistry

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