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Publication Abstract from PubMed

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 A resolution. The structure consists of 12 alpha-helices with characteristic N-terminal beta-strands (Nbeta) and forms a V-shaped-twist dimer in the asymmetric unit. Structure-based mutagenesis revealed that Nbeta and the alpha1 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.

Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1-interacting protein facilitating virus replication.,Chung WC, Kim J, Kim BC, Kang HR, Son J, Ki H, Hwang KY, Song MJ IUCrJ. 2018 Oct 31;5(Pt 6):866-879. doi: 10.1107/S2052252518013854. eCollection, 2018 Nov 1. PMID:30443370^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.