title: Viral and cellular proteins containing FGDF motifs bind G3BP to block stress granule formation.
abstract: The Ras-GAP SH3 domain-binding proteins (G3BP) are essential regulators of the formation of stress granules (SG), cytosolic aggregates of proteins and RNA that are induced upon cellular stress, such as virus infection. Many viruses, including Semliki Forest virus (SFV), block SG induction by targeting G3BP. In this work, we demonstrate that the G3BP-binding motif of SFV nsP3 consists of two FGDF motifs, in which both phenylalanine and the glycine residue are essential for binding. In addition, we show that binding of the cellular G3BP-binding partner USP10 is also mediated by an FGDF motif. Overexpression of wt USP10, but not a mutant lacking the FGDF-motif, blocks SG assembly. Further, we identified FGDF-mediated G3BP binding site in herpes simplex virus (HSV) protein ICP8, and show that ICP8 binding to G3BP also inhibits SG formation, which is a novel function of HSV ICP8. We present a model of the three-dimensional structure of G3BP bound to an FGDF-containing peptide, likely representing a binding mode shared by many proteins to target G3BP.
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Marc D
authors: MD
authors: Panas
authors: Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Tim
authors: T
authors: Schulte
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Bastian
authors: B
authors: Thaa
authors: Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Tatiana
authors: T
authors: Sandalova
authors: Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Nancy
authors: N
authors: Kedersha
authors: Science for Life Laboratory, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors: Adnane
authors: A
authors: Achour
authors: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
authors: Gerald M
authors: GM
authors: McInerney
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003594:Cytoplasmic Granules / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C045462:ICP8 protein, Simplexvirus; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; D014764:Viral Proteins; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases