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A substrate binding model for the KEOPS tRNA modifying complex.

Jonah BeenstockSamara Mishelle OnaJennifer PoratStephen OrlickyLeo C K WanDerek F CeccarelliPierre MaisonneuveRachel K SzilardZhe YinDheva SetiaputraDaniel Y L MaoMorgan KhanShaunak RavalDavid C SchriemerMark A BayfieldDaniel DurocherFrank Sicheri
Published in: Nature communications (2020)
The KEOPS complex, which is conserved across archaea and eukaryotes, is composed of four core subunits; Pcc1, Kae1, Bud32 and Cgi121. KEOPS is crucial for the fitness of all organisms examined. In humans, pathogenic mutations in KEOPS genes lead to Galloway-Mowat syndrome, an autosomal-recessive disease causing childhood lethality. Kae1 catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine, but the precise roles of all other KEOPS subunits remain an enigma. Here we show using structure-guided studies that Cgi121 recruits tRNA to KEOPS by binding to its 3' CCA tail. A composite model of KEOPS bound to tRNA reveals that all KEOPS subunits form an extended tRNA-binding surface that we have validated in vitro and in vivo to mediate the interaction with the tRNA substrate and its modification. These findings provide a framework for understanding the inner workings of KEOPS and delineate why all KEOPS subunits are essential.
Keyphrases
  • physical activity
  • transcription factor
  • genome wide
  • young adults
  • case report
  • binding protein
  • multidrug resistant
  • dna methylation
  • gram negative
  • case control
  • genome wide identification