title: Mechanisms of translational regulation by a human eIF5-mimic protein.
abstract: The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, eIF5 binds eIF2/GTP/Met-tRNA(i)(Met) ternary complex (TC), promoting its recruitment to 40S ribosomal subunits. Secondly, its GTPase activating function promotes eIF2 dissociation for ribosomal subunit joining. Finally, eIF5 GDP dissociation inhibition (GDI) activity can antagonize eIF2 reactivation by competing with the eIF2 guanine exchange factor (GEF), eIF2B. The C-terminal domain (CTD) of eIF5, a W2-type HEAT domain, mediates its interaction with eIF2. Here, we characterize a related human protein containing MA3- and W2-type HEAT domains, previously termed BZW2 and renamed here as eIF5-mimic protein 1 (5MP1). Human 5MP1 interacts with eIF2 and eIF3 and inhibits general and gene-specific translation in mammalian systems. We further test whether 5MP1 is a mimic or competitor of the GEF catalytic subunit eIF2Bε or eIF5, using yeast as a model. Our results suggest that 5MP1 interacts with yeast eIF2 and promotes TC formation, but inhibits TC binding to the ribosome. Moreover, 5MP1 is not a GEF but a weak GDI for yeast eIF2. We propose that 5MP1 is a partial mimic and competitor of eIF5, interfering with the key steps by which eIF5 regulates eIF2 function.
authors: Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
authors: Chingakham Ranjit
authors: CR
authors: Singh
authors: Ryosuke
authors: R
authors: Watanabe
authors: Donghui
authors: D
authors: Zhou
authors: Martin D
authors: MD
authors: Jennings
authors: Akira
authors: A
authors: Fukao
authors: Bumjun
authors: B
authors: Lee
authors: Yuka
authors: Y
authors: Ikeda
authors: John A
authors: JA
authors: Chiorini
authors: Susan G
authors: SG
authors: Campbell
authors: Mark P
authors: MP
authors: Ashe
authors: Toshinobu
authors: T
authors: Fujiwara
authors: Ronald C
authors: RC
authors: Wek
authors: Graham D
authors: GD
authors: Pavitt
authors: Katsura
authors: K
authors: Asano
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000032:analysis / Q000378:metabolism*; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006153:Guanosine Diphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018716:Molecular Mimicry; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D051701:Activating Transcription Factor 4; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D020717:Eukaryotic Initiation Factor-2B; D039621:Eukaryotic Initiation Factor-3; D039642:Eukaryotic Initiation Factors; D006153:Guanosine Diphosphate; D010448:Peptide Initiation Factors; D017346:Protein Serine-Threonine Kinases; D016601:RNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C568809:BZW2 protein, human; C512912:GCN2 protein, S cerevisiae