Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-08211-9
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Funding
- U.S. National Institutes of Health [R35-GM122575]
- Geoffrey Beene Cancer Research Center
- National Cancer Institute [P30-CA008748]
- National Institutes of Health [P41GM103403, HEI-S10RR029205]
- Department of Energy [DE-AC02-06CH11357]
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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 angstrom crystal structure of Tpt1 in a productmimetic 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.
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