Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication
| العنوان: | Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication |
|---|---|
| المؤلفون: | Kwang Yeon Hwang, Jonghyeon Son, Junsoo Kim, Moon Jung Song, Byungchul Kim, Hosam Ki, Woo Chang Chung, Hye Ri Kang |
| المصدر: | IUCrJ, Vol 5, Iss 6, Pp 866-879 (2018) IUCrJ |
| بيانات النشر: | International Union of Crystallography (IUCr), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, viral PARP-1-interacting protein, viruses, Poly ADP ribose polymerase, medicine.disease_cause, Biochemistry, open reading frame 49, 03 medical and health sciences, Viral life cycle, Kaposi’s sarcoma-associated herpesvirus, medicine, General Materials Science, Kaposi's sarcoma-associated herpesvirus, Nuclear protein, lcsh:Science, Polymerase, X-ray crystallography, biology, Chemistry, virus diseases, General Chemistry, Condensed Matter Physics, Research Papers, structure determination, Cell biology, 030104 developmental biology, Lytic cycle, Viral replication, poly(ADP-ribose) polymerase 1, biology.protein, murine gammaherpesvirus 68, lcsh:Q, Nuclear localization sequence |
| الوصف: | The structure of a viral poly(ADP-ribose) polymerase 1 (PARP-1)-interacting protein from murine gammaherpesvirus 68 (MHV-68) is reported. Structure-based mutagenesis revealed residues that are critical for function and interaction with PARP-1, and a recombinant MHV-68 harboring mutations of these three residues showed severely attenuated viral replication in infected cells and mice. A homologous vPIP protein of Kaposi’s sarcoma-associated herpesvirus also interacted with PAPR-1 and disrupted its inhibitory function, suggesting the conserved molecular mechanism of vPIPs to facilitate viral replication among gammaherpesviruses. 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 Å resolution. The structure consists of 12 α-helices with characteristic N-terminal β-strands (Nβ) and forms a V-shaped-twist dimer in the asymmetric unit. Structure-based mutagenesis revealed that Nβ and the α1 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. |
| تدمد: | 2052-2525 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8464b9da4a9b235ca69670484622d59a https://doi.org/10.1107/s2052252518013854 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....8464b9da4a9b235ca69670484622d59a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20522525 |
|---|