title: The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader.
abstract: Transport of the essential amino acids arginine and lysine is critical for the survival of mammalian cells. The adaptive response to nutritional stress involves increased translation of the arginine/lysine transporter (cat-1) mRNA via an internal ribosome entry site (IRES) within the mRNA leader. Induction of cat-1 IRES activity requires both translation of a small upstream open reading frame (uORF) within the IRES and phosphorylation of the translation initiation factor eIF2alpha. We show here that translation of the upstream ORF unfolds an inhibitory structure in the mRNA leader, eliciting a conformational change that yields an active IRES. The IRES, whose activity is induced by amino acid starvation, is created by RNA-RNA interactions between the 5' end of the leader and downstream sequences. This study suggests that the structure of the IRES is dynamic and regulation of this RNA structure is a mechanism of translational control.
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Yaman
authors.forename: James
authors.initials: J
authors.lastname: Fernandez
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.forename: Mark
authors.initials: M
authors.lastname: Caprara
authors.forename: Anton A
authors.initials: AA
authors.lastname: Komar
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.forename: Lingyin
authors.initials: L
authors.lastname: Zhou
authors.forename: Martin D
authors.initials: MD
authors.lastname: Snider
authors.forename: Donalyn
authors.initials: D
authors.lastname: Scheuner
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000172:deficiency*; D001483:Base Sequence / Q000235:genetics; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005057:Eukaryotic Cells / Q000166:cytology / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000172:deficiency*; D008954:Models, Biological; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016366:Open Reading Frames / Q000235:genetics*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000235:genetics; D051381:Rats; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D020121:5' Untranslated Regions; D027201:Cationic Amino Acid Transporter 1; D004268:DNA-Binding Proteins; D039642:Eukaryotic Initiation Factors; D014157:Transcription Factors; D001120:Arginine; D008239:Lysine