Unraveling blunt-end RNA binding and ATPase-driven translocation activities of the RIG-I family helicase LGP2

Author:

Lee Kuan-Ying12,Craig Candice12,Patel Smita S1ORCID

Affiliation:

1. Department of Biochemistry and Molecular Biology, Rutgers University, Robert Wood Johnson Medical School , Piscataway, NJ 08854 , USA

2. Graduate School of Biomedical Sciences at the Robert Wood Johnson Medical School of Rutgers University , 08854, USA

Abstract

Abstract The RIG-I family helicases, comprising RIG-I, MDA5 and LGP2, are cytoplasmic RNA sensors that trigger an antiviral immune response by specifically recognizing foreign RNAs. While LGP2 lacks the signaling domain necessary for immune activation, it plays a vital role in regulating the RIG-I/MDA5 signaling pathway. In this study, we investigate the mechanisms underlying this regulation by examining the oligomeric state, RNA binding specificity, and translocation activity of human LGP2 and the impact of ATPase activity. We show that LGP2, like RIG-I, prefers binding blunt-ended double-stranded (ds) RNAs over internal dsRNA regions or RNA overhangs and associates with blunt-ends faster than with overhangs. Unlike RIG-I, a 5′-triphosphate (5′ppp), Cap0, or Cap1 RNA-end does not influence LGP2’s RNA binding affinity. LGP2 hydrolyzes ATP in the presence of RNA but at a 5–10 fold slower rate than RIG-I. Nevertheless, LGP2 uses its ATPase activity to translocate and displace biotin-streptavidin interactions. This activity is significantly hindered by a methylated RNA patch, particularly on the 3′-strand, suggesting a 3′-strand tracking mechanism like RIG-I. The preference of LGP2 for blunt-end RNA binding, its insensitivity to Cap0/Cap1 modification, and its translocation/protein displacement ability have substantial implications for how LGP2 regulates the RNA sensing process by MDA5/RIG-I.

Funder

National Institute of General Medical Sciences

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference47 articles.

1. Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors;Onomoto;Cell. Mol. Immunol.,2021

2. The molecular mechanism of RIG-I activation and signaling;Thoresen;Immunol. Rev.,2021

3. MDA5 and LGP2: accomplices and antagonists of antiviral signal transduction;Rodriguez;J. Virol.,2014

4. MDA5 cooperatively forms dimers and ATP-sensitive filaments upon binding double-stranded RNA;Berke;EMBO J.,2012

5. Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments;Peisley;Biophys. J.,2012

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3