A substrate binding model for the KEOPS tRNA modifying complex

Author:

Beenstock Jonah,Ona Samara Mishelle,Porat Jennifer,Orlicky Stephen,Wan Leo C. K.,Ceccarelli Derek F.ORCID,Maisonneuve PierreORCID,Szilard Rachel K.,Yin Zhe,Setiaputra Dheva,Mao Daniel Y. L.,Khan Morgan,Raval Shaunak,Schriemer David C.ORCID,Bayfield Mark A.,Durocher DanielORCID,Sicheri FrankORCID

Abstract

AbstractThe 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.

Funder

Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada

Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada

Gouvernement du Canada | Canadian Institutes of Health Research

The Krembil foundation

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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