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Molecular architecture of the human tRNA ligase complex

Alena Kroupova, View ORCID ProfileFabian Ackle, Franziska M. Boneberg, Alessia Chui, Stefan Weitzer, Marco Faini, Alexander Leitner, Ruedi Aebersold, Javier Martinez, View ORCID ProfileMartin Jinek
doi: https://doi.org/10.1101/2021.07.11.451954
Alena Kroupova
1Department of Biochemistry, University of Zurich, Zurich, 8057, Switzerland
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Fabian Ackle
1Department of Biochemistry, University of Zurich, Zurich, 8057, Switzerland
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Franziska M. Boneberg
1Department of Biochemistry, University of Zurich, Zurich, 8057, Switzerland
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Alessia Chui
1Department of Biochemistry, University of Zurich, Zurich, 8057, Switzerland
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Stefan Weitzer
2Max Perutz Labs, Vienna BioCenter (VBC), Vienna, 1030, Austria
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Marco Faini
3Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, 8093, Switzerland
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Alexander Leitner
3Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, 8093, Switzerland
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Ruedi Aebersold
3Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, 8093, Switzerland
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Javier Martinez
2Max Perutz Labs, Vienna BioCenter (VBC), Vienna, 1030, Austria
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Martin Jinek
1Department of Biochemistry, University of Zurich, Zurich, 8057, Switzerland
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  • ORCID record for Martin Jinek
  • For correspondence: jinek@bioc.uzh.ch
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ABSTRACT

RtcB enzymes are RNA ligases that play essential roles in tRNA splicing, unfolded protein response, and RNA repair. In metazoa, RtcB functions as part of a five-subunit tRNA ligase complex (tRNA-LC) along with Ddx1, Cgi-99, Fam98B and Ashwin. The human tRNA-LC or its individual subunits have been implicated in additional cellular processes including microRNA maturation, viral replication, DNA double-strand break repair and mRNA transport. Here we present a biochemical analysis of the inter-subunit interactions within the human tRNA-LC along with crystal structures of the catalytic subunit RTCB and the N-terminal domain of CGI-99. We show that the core of the human tRNA-LC is assembled from RTCB and the C-terminal alpha-helical regions of DDX1, CGI-99, and FAM98B, all of which are required for complex integrity. The N-terminal domain of CGI-99 displays structural homology to calponin-homology domains, and CGI-99 and FAM98B associate via their N-terminal domains to form a stable subcomplex. The crystal structure of GMP-bound RTCB reveals divalent metal coordination geometry in the active site, providing insights into its catalytic mechanism. Collectively, these findings shed light on the molecular architecture and mechanism of the human tRNA ligase complex, and provide a structural framework for understanding its functions in cellular RNA metabolism.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted July 12, 2021.
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Molecular architecture of the human tRNA ligase complex
Alena Kroupova, Fabian Ackle, Franziska M. Boneberg, Alessia Chui, Stefan Weitzer, Marco Faini, Alexander Leitner, Ruedi Aebersold, Javier Martinez, Martin Jinek
bioRxiv 2021.07.11.451954; doi: https://doi.org/10.1101/2021.07.11.451954
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Molecular architecture of the human tRNA ligase complex
Alena Kroupova, Fabian Ackle, Franziska M. Boneberg, Alessia Chui, Stefan Weitzer, Marco Faini, Alexander Leitner, Ruedi Aebersold, Javier Martinez, Martin Jinek
bioRxiv 2021.07.11.451954; doi: https://doi.org/10.1101/2021.07.11.451954

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