Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication

Woo Chang Chung, Junsoo Kim, Byung Chul Kim, Hye Ri Kang, Jonghyeon Son, Hosam Ki, Kwang Yeon Hwang, Moon Jung Song

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)866-879
Number of pages14
JournalIUCrJ
Volume5
DOIs
Publication statusPublished - 2018 Jan 1

Fingerprint

Administrative data processing
ribose
adenosine diphosphate
Poly(ADP-ribose) Polymerases
viruses
Virus Replication
Viruses
proteins
Proteins
Transcription
helices
Mutagenesis
mutagenesis
disrupting
Nuclear Proteins
Dimers
Adenosine Diphosphate
mutations
Poly (ADP-Ribose) Polymerase-1
Life cycle

Keywords

  • Kaposi's sarcoma-associated herpesvirus
  • murine gammaherpesvirus 68
  • open reading frame 49
  • poly(ADP-ribose) polymerase 1
  • structure determination
  • viral PARP-1-interacting protein
  • X-ray crystallography

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry
  • Materials Science(all)
  • Condensed Matter Physics

Cite this

Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication. / Chung, Woo Chang; Kim, Junsoo; Kim, Byung Chul; Kang, Hye Ri; Son, Jonghyeon; Ki, Hosam; Hwang, Kwang Yeon; Song, Moon Jung.

In: IUCrJ, Vol. 5, 01.01.2018, p. 866-879.

Research output: Contribution to journalArticle

Chung, Woo Chang ; Kim, Junsoo ; Kim, Byung Chul ; Kang, Hye Ri ; Son, Jonghyeon ; Ki, Hosam ; Hwang, Kwang Yeon ; Song, Moon Jung. / Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication. In: IUCrJ. 2018 ; Vol. 5. pp. 866-879.
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