title: Structural switch of lysyl-tRNA synthetase between translation and transcription.
abstract: Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap(4)A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Yifat
authors.initials: Y
authors.lastname: Ofir-Birin
authors.forename: Pengfei
authors.initials: P
authors.lastname: Fang
authors.forename: Steven P
authors.initials: SP
authors.lastname: Bennett
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Inbal
authors.initials: I
authors.lastname: Rachmin
authors.forename: Ryan
authors.initials: R
authors.lastname: Shapiro
authors.forename: Jing
authors.initials: J
authors.lastname: Song
authors.forename: Arie
authors.initials: A
authors.lastname: Dagan
authors.forename: Jorge
authors.initials: J
authors.lastname: Pozo
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.forename: Alan G
authors.initials: AG
authors.lastname: Marshall
authors.forename: Paul
authors.initials: P
authors.lastname: Schimmel
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.forename: Hovav
authors.initials: H
authors.lastname: Nechushtan
authors.forename: Ehud
authors.initials: E
authors.lastname: Razin
authors.forename: Min
authors.initials: M
authors.lastname: Guo
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D015226:Dinucleoside Phosphates / Q000378:metabolism; D006801:Humans; D008250:Lysine-tRNA Ligase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D051381:Rats; D015290:Second Messenger Systems; D014158:Transcription, Genetic
chemical_list: C575685:AIMP2 protein, human; D002352:Carrier Proteins; D015226:Dinucleoside Phosphates; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D009687:Nuclear Proteins; C020733:diadenosine tetraphosphate; D008250:Lysine-tRNA Ligase