A substrate binding model for the KEOPS tRNA modifying complex.

Autor: Beenstock J; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada., Ona SM; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Porat J; Department of Biology, York University, Toronto, ON, Canada., Orlicky S; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada., Wan LCK; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Ceccarelli DF; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada., Maisonneuve P; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada., Szilard RK; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada., Yin Z; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.; Department of Biochemistry, University of Toronto, Toronto, ON, Canada., Setiaputra D; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada., Mao DYL; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada., Khan M; Department of Chemistry, University of Calgary, Calgary, AB, Canada., Raval S; Department of Chemistry, University of Calgary, Calgary, AB, Canada., Schriemer DC; Department of Chemistry, University of Calgary, Calgary, AB, Canada.; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, Canada., Bayfield MA; Department of Biology, York University, Toronto, ON, Canada., Durocher D; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada., Sicheri F; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. sicheri@lunenfeld.ca.; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. sicheri@lunenfeld.ca.; Department of Biochemistry, University of Toronto, Toronto, ON, Canada. sicheri@lunenfeld.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Dec 04; Vol. 11 (1), pp. 6233. Date of Electronic Publication: 2020 Dec 04.
DOI: 10.1038/s41467-020-19990-5
Abstrakt: 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.
Databáze: MEDLINE
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