Structure of tRNA splicing enzyme Tpt1 illuminates the mechanism of RNA 2′-PO4 recognition and ADP-ribosylation

Ankan Banerjee, Annum Munir, Leonora Abdullahu, Masad J. Damha, Yehuda Goldgur and Stewart Shuman ()
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Ankan Banerjee: Sloan-Kettering Institute
Annum Munir: Sloan-Kettering Institute
Leonora Abdullahu: McGill University
Masad J. Damha: McGill University
Yehuda Goldgur: Sloan-Kettering Institute
Stewart Shuman: Sloan-Kettering Institute

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract Tpt1 is an essential agent of fungal tRNA splicing that removes the 2′-PO4 at the splice junction generated by fungal tRNA ligase. Tpt1 catalyzes a unique two-step reaction whereby the 2′-PO4 attacks NAD+ to form an RNA-2′-phospho-ADP-ribosyl intermediate that undergoes transesterification to yield 2′-OH RNA and ADP-ribose-1″,2″-cyclic phosphate products. Because Tpt1 is inessential in exemplary bacterial and mammalian taxa, Tpt1 is seen as an attractive antifungal target. Here we report a 1.4 Å crystal structure of Tpt1 in a product-mimetic complex with ADP-ribose-1″-phosphate in the NAD+ site and pAp in the RNA site. The structure reveals how Tpt1 recognizes a 2′-PO4 RNA splice junction and the mechanism of RNA phospho-ADP-ribosylation. This study also provides evidence that a bacterium has an endogenous phosphorylated substrate with which Tpt1 reacts.

Date: 2019
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DOI: 10.1038/s41467-018-08211-9

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