Structure and two-metal mechanism of a eukaryal nick-sealing RNA ligase

Unciuleac, Mihaela-Carmen; Goldgur, Yehuda; Shuman, Stewart

doi:10.1073/pnas.1516536112

Title: Structure and two-metal mechanism of a eukaryal nick-sealing RNA ligase

Journal Article · Wed Oct 28 00:00:00 EDT 2015 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1516536112· OSTI ID:1226368

Unciuleac, Mihaela-Carmen ^[1]; Goldgur, Yehuda ^[1]; Shuman, Stewart ^[1]

Sloan-Kettering Inst., New York, NY (United States)

ATP-dependent RNA ligases are agents of RNA repair that join 3'-OH and 5'-PO₄RNA ends.Naegleria gruberiRNA ligase (NgrRnl) exemplifies a family of RNA nick-sealing enzymes found in bacteria, viruses, and eukarya. Crystal structures of NgrRnl at three discrete steps along the reaction pathway—covalent ligase-(lysyl-Nζ)–AMP•Mn²⁺intermediate; ligase•ATP•(Mn²⁺)₂Michaelis complex; and ligase•Mn²⁺complex—highlight a two-metal mechanism of nucleotidyl transfer, whereby (i) an enzyme-bound “catalytic” metal coordination complex lowers the pK_aof the lysine nucleophile and stabilizes the transition state of the ATP α phosphate; and (ii) a second metal coordination complex bridges the β- and γ-phosphates. The NgrRnl N domain is a distinctively embellished oligonucleotide-binding (OB) fold that engages the γ-phosphate and associated metal complex and orients the pyrophosphate leaving group for in-line catalysis with stereochemical inversion at the AMP phosphate. The unique domain architecture of NgrRnl fortifies the theme that RNA ligases have evolved many times, and independently, by fusions of a shared nucleotidyltransferase domain to structurally diverse flanking modules. In conclusion, the mechanistic insights to lysine adenylylation gained from the NgrRnl structures are likely to apply broadly to the covalent nucleotidyltransferase superfamily of RNA ligases, DNA ligases, and RNA capping enzymes.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; Memorial Sloan Kettering Cancer Center

Grant/Contract Number:: GM42498; P30-CA008748

OSTI ID:: 1226368

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, Issue 45; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 18 works

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