Structural and mechanistic insights into activation of the human RNA ligase RTCB by Archease

Janina Lara Gerber, Suria Itzel Morales Guzmán, Lorenz Worf, Petra Hubbe, Jürgen Kopp and Jirka Peschek ()
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Janina Lara Gerber: Biochemistry Center (BZH)
Suria Itzel Morales Guzmán: Biochemistry Center (BZH)
Lorenz Worf: Biochemistry Center (BZH)
Petra Hubbe: Biochemistry Center (BZH)
Jürgen Kopp: Biochemistry Center (BZH)
Jirka Peschek: Biochemistry Center (BZH)

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract RNA ligases of the RTCB-type play an essential role in tRNA splicing, the unfolded protein response and RNA repair. RTCB is the catalytic subunit of the pentameric human tRNA ligase complex. RNA ligation by the tRNA ligase complex requires GTP-dependent activation of RTCB. This active site guanylylation reaction relies on the activation factor Archease. The mechanistic interplay between both proteins has remained unknown. Here, we report a biochemical and structural analysis of the human RTCB-Archease complex in the pre- and post-activation state. Archease reaches into the active site of RTCB and promotes the formation of a covalent RTCB-GMP intermediate through coordination of GTP and metal ions. During the activation reaction, Archease prevents futile RNA substrate binding to RTCB. Moreover, monomer structures of Archease and RTCB reveal additional states within the RNA ligation mechanism. Taken together, we present structural snapshots along the reaction cycle of the human tRNA ligase.

Date: 2024
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DOI: 10.1038/s41467-024-46568-2

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