A second catalytic metal ion in a group I ribozyme

Lara B. Weinstein, B. C. N. M. Jones, Richard Cosstick and Thomas R. Cech ()
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Lara B. Weinstein: Howard Hughes Medical Institute, University of Colorado
B. C. N. M. Jones: Robert Robinson Laboratory, University of Liverpool
Richard Cosstick: Robert Robinson Laboratory, University of Liverpool
Thomas R. Cech: Howard Hughes Medical Institute, University of Colorado

Nature, 1997, vol. 388, issue 6644, 805-808

Abstract: Abstract Although only a subset of protein enzymes depend on the presence of a metal ion for their catalytic function, all naturally occurring RNA enzymes require metal ions to stabilize theirstructure and for catalytic competence1. In the self-splicing group I intron from Tetrahymena thermophila2, several divalent metals can serve structural roles, but only Mg2+ and Mn2+ promote splice-site cleavage and exon ligation3,4. A study of a ribozyme reaction analogous to 5′-splice-site cleavage by guanosine uncovered the first metal ion with a definitive role in catalysis. Substitution of the 3′-oxygen of the leaving group with sulphur resulted in a metal-specificity switch, indicating an interaction between the leaving group and the metal ion5. Here we use 3′-(thioinosylyl)-(3′ → 5′)-uridine6, IspU, as a substrate in a reaction that emulates exon ligation. Activity requires the addition of a thiophilic metal ion (Cd2+ or Mn2+), providing evidence for stabilization of the leaving group by a metal ion in that step of splicing. Based on the principle of microscopic reversibility, this metal ion activates the nucleophilic 3′-hydroxyl of guanosine in the first step of splicing, supporting the model of a two-metal-ion active site7.

Date: 1997
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DOI: 10.1038/42076

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