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Open Biol. 2016 Jul;6(7). pii: 160078. doi: 10.1098/rsob.160078.

Combined structural, biochemical and cellular evidence demonstrates that both FGDF motifs in alphavirus nsP3 are required for efficient replication.

Author information

1
Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden Department of Infectious Diseases, Karolinska University Hospital, Solna, Stockholm, Sweden.
2
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
3
Division of Rheumatology, Immunology and Allergy, Harvard Medical School and Brigham and Women's Hospital, Smith 652; 1 Jimmy Fund Way, Boston, MA 02115, USA.
4
Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden Department of Infectious Diseases, Karolinska University Hospital, Solna, Stockholm, Sweden adnane.achour@ki.se.
5
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden gerald.mcinerney@ki.se.

Abstract

Recent findings have highlighted the role of the Old World alphavirus non-structural protein 3 (nsP3) as a host defence modulator that functions by disrupting stress granules, subcellular phase-dense RNA/protein structures formed upon environmental stress. This disruption mechanism was largely explained through nsP3-mediated recruitment of the host G3BP protein via two tandem FGDF motifs. Here, we present the 1.9 Å resolution crystal structure of the NTF2-like domain of G3BP-1 in complex with a 25-residue peptide derived from Semliki Forest virus nsP3 (nsP3-25). The structure reveals a poly-complex of G3BP-1 dimers interconnected through the FGDF motifs in nsP3-25. Although in vitro and in vivo binding studies revealed a hierarchical interaction of the two FGDF motifs with G3BP-1, viral growth curves clearly demonstrated that two intact FGDF motifs are required for efficient viral replication. Chikungunya virus nsP3 also binds G3BP dimers via a hierarchical interaction, which was found to be critical for viral replication. These results highlight a conserved molecular mechanism in host cell modulation.

KEYWORDS:

innate immunity; protein structure–function; stress response; virus–host interaction

PMID:
27383630
PMCID:
PMC4967826
DOI:
10.1098/rsob.160078
[Indexed for MEDLINE]
Free PMC Article

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