NMR studies on the structure and function of the influenza virus polymerase PA, PB2 and fanconi anemia-associated protein = 인플루엔자 바이러스의 PA와 PB2 중합효소 및 판코니 빈혈 증후군 단백질의 구조와 기능에 대한 NMR 연구

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Influenza RNA polymerase is composed of three subunits, PA, PB1, and PB2, which interact with each other for transcription and replication of the viral RNA genome in the nucleus of infected cells. PB2’s RNA-binding 627-domain (residues 535-693), located in the C-terminus, presents a highly basic surface around residue K627 and has been proposed to interact with viral or cellular factors, resulting in host adaptation. However, the function of this domain is not yet characterized in detail. In this study, I identified RNA-binding activity and RNA-binding surfaces in both the N-terminal and basic C-terminal regions of PB2 using NMR experiments. Through mutagenesis studies, I confirmed which residues directly interact with RNA and mapped their locations on the RNA-binding surface. In addition, by luciferase activity assays, I showed that influenza virus polymerase activity may correlate with the interaction between PB2 and RNA. Representative host adaptive mutations Q591K/R and E627K were found to be located on the RNA-binding surface and were confirmed to directly interact with RNA and to affect polymerase activity. From these results, I suggest that influenza virus polymerase activity may be regulated through the interaction between PB2’s 627-domain and RNA and that consequently host adaptation of the virus may be influenced. Influenza A viruses are viral pathogens that cause both seasonal influenza epidemics and global pandemics. Although there are effective drugs such as the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza), influenza virus can have resistance to these drugs by the long-term use. Therefore, new anti-viral drug have to be developed to prevent the epidemic and pandemic by influenza virus. In particular, influenza virus polymerase PA subunit contains the endonuclease activity, which creates a capped RNA primer during viral transcription, and high conserved sequence among influenza strains. On account of this significance, PA ...
Choi, Byong-Seokresearcher최병석
한국과학기술원 : 화학과,
Issue Date
568645/325007  / 020085322

학위논문(박사) - 한국과학기술원 : 화학과, 2014.2, [ viii, 67 p. ]


Influenza RNA polymerase; FAAP20 단백질; 판코니 빈혈; PA endonuclease 도메인; PB2 RNA 결합 도메인; 인플루엔자 RNA 중합효소; PB2 RNA-binding domain; PA endonuclease domain; Fanconi-anemia; FAAP20 protein

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