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A substrate binding model for the KEOPS tRNA modifying complex
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DOI：10.1038/s41467-020-19990-5.png)
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Abstract
En 中文
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 N-6-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. KEOPS is an evolutionary conserved complex with a core of four core subunits-Pcc1, Kae1, Bud32 and Cgi121-that catalyzes the universal and essential tRNA modification N-6-threonylcarbamoyl adenosine (t(6)A). Here the authors describe a Cgi121-tRNA crystal structure and new composite model of the KEOPS holo-enzyme-substrate complex that shed light on the t(6)A catalytic cycle and its regulation.
Keywords:
THREONYLCARBAMOYLADENOSINE T(6)A
SACCHAROMYCES-CEREVISIAE
BIOSYNTHESIS
TRANSLATION
DATABASE
TRANSCRIPTION
EKC/KEOPS
MECHANISM
SOFTWARE
SYSTEM
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