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Coupled 5′ Nucleotide Recognition and Processivity in Xrn1-Mediated mRNA Decay

2011; Elsevier BV; Volume: 41; Issue: 5 Linguagem: Inglês

10.1016/j.molcel.2011.02.004

1097-4164

Martin Jínek, Scott M. Coyle, Jennifer A. Doudna,

DNA and Nucleic Acid Chemistry

Messenger RNA decay plays a central role in the regulation and surveillance of eukaryotic gene expression. The conserved multidomain exoribonuclease Xrn1 targets cytoplasmic RNA substrates marked by a 5′ monophosphate for processive 5′-to-3′ degradation by an unknown mechanism. Here, we report the crystal structure of an Xrn1-substrate complex. The single-stranded substrate is held in place by stacking of the 5′-terminal trinucleotide between aromatic side chains while a highly basic pocket specifically recognizes the 5′ phosphate. Mutations of residues involved in binding the 5′-terminal nucleotide impair Xrn1 processivity. The substrate recognition mechanism allows Xrn1 to couple processive hydrolysis to duplex melting in RNA substrates with sufficiently long single-stranded 5′ overhangs. The Xrn1-substrate complex structure thus rationalizes the exclusive specificity of Xrn1 for 5′-monophosphorylated substrates, ensuring fidelity of mRNA turnover, and posits a model for translocation-coupled unwinding of structured RNA substrates.