Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication
- Authors
- Chung, Woo-Chang; Kim, Junsoo; Kim, Byung Chul; Kang, Hye-Ri; Son, JongHyeon; Ki, Hosam; Hwang, Kwang Yeon; Song, Moon Jung
- Issue Date
- 11월-2018
- Publisher
- INT UNION CRYSTALLOGRAPHY
- Keywords
- viral PARP-1-interacting protein; open reading frame 49; poly(ADP-ribose) polymerase 1; murine gammaherpesvirus 68; Kaposi' s sarcoma-associated herpesvirus; structure determination; X-ray crystallography
- Citation
- IUCRJ, v.5, pp.866 - 879
- Indexed
- SCIE
SCOPUS
- Journal Title
- IUCRJ
- Volume
- 5
- Start Page
- 866
- End Page
- 879
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/71962
- DOI
- 10.1107/S2052252518013854
- ISSN
- 2052-2525
- Abstract
- Poly(ADP-ribose) polymerase 1 (PARP-1), an enzyme that modifies nuclear proteins by poly(ADP-ribosyl) ation, regulates various cellular activities and restricts the lytic replication of oncogenic gammaherpesviruses by inhibiting the function of replication and transcription activator (RTA), a key switch molecule of the viral life cycle. A viral PARP-1-interacting protein (vPIP) encoded by murine gammaherpesvirus 68 (MHV-68) orf49 facilitates lytic replication by disrupting interactions between PARP-1 and RTA. Here, the structure of MHV-68 vPIP was determined at 2.2 angstrom resolution. The structure consists of 12 alpha-helices with characteristic N-terminal beta-strands (N beta) and forms a V-shaped-twist dimer in the asymmetric unit. Structure-based mutagenesis revealed that N beta and the alpha 1 helix (residues 2-26) are essential for the nuclear localization and function of vPIP; three residues were then identified (Phe5, Ser12 and Thr16) that were critical for the function of vPIP and its interaction with PARP-1. A recombinant MHV-68 harboring mutations of these three residues showed severely attenuated viral replication both in vitro and in vivo. Moreover, ORF49 of Kaposi's sarcoma-associated herpesvirus also directly interacted with PARP-1, indicating a conserved mechanism of action of vPIPs. The results elucidate the novel molecular mechanisms by which oncogenic gammaherpesviruses overcome repression by PARP-1 using vPIPs.
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Collections - Graduate School > Department of Biotechnology > 1. Journal Articles
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