Structural basis for retroviral integration into nucleosomes

Maskell, D. P., et al. Nature 523, 366-369 (2015).

Speaker: Jyun-Cyuan Chang (張鈞筌)             Time: 13:00~14:00, Sep 30, 2015

Commentator: Dr. Wen-Yih Jeng (鄭文義 老師)    Place: Room 601

Abstract

Retroviral integration into the host cell chromosome is an essential step in replication of retrovirus. Integration is catalyzed by integrase (IN) which was assembled on viral DNA ends in a stable complex, known as the intasome (1). The intasome engages nucleosome DNA to carry out DNA strand transfer. The molecular basis between intasome and nucleosome is still unclear. The PFV intasome displayed strong activity of integration with recombinant nucleosomes. In this study, prototype foamy virus (PFV) intasome was used as a model of retroviral activity and displayed strong activity of integration with recombinant nucleosomes. However, integration into deproteinized nucleosomal DNA was less efficient and losing specific integration site. In previous studies, the PFV intasome contains two types of IN which were inner and outer IN units. The function of inner IN units is to assemble on viral DNA ends and to form the target DNA-binding groove. The function of outer IN units is to attach to inner IN by the catalytic core domain (2). Single-particle cryo-electron microscopy  structure reveals that the intasome-nucleosome interface involves both the gyre of nucleosomal DNA and one H2A-H2B heterodimer which interact with IN. The nuclesomal DNA in intasome-nucleosome complex is different from the structure of free nucleosome. The DNA deforms conformation to match target DNA-binding groove of the intasome. The authors further showed that the amino acid mutations on the intasome-nucleosome surface attenuate the ability of the intasome to engage nucleosomes in vitro. In this study, the authors defined the structural basis of retroviral DNA integration and will allow modeling of the retroviral intasome to aid in the development of antiretroviral drugs.

References:

1.         Hare, S., Gupta, S.S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232-6 (2010).

2.         Pruss D, Bushman FD, & Wolffe AP (1994) Human immunodeficiency virus integrase directs integration to sites of severe DNA distortion within the nucleosome core. Proceedings of the National Academy of Sciences of the United States of America 91(13):5913-5917.