Letter

Nature 461, 823-827 (8 October 2009) | doi:10.1038/nature08433; Received 16 April 2009; Accepted 17 August 2009

Structural insights into mechanisms of the small RNA methyltransferase HEN1

Ying Huang1, Lijuan Ji2, Qichen Huang1, Dmitry G. Vassylyev1, Xuemei Chen2 & Jin-Biao Ma1,3

  1. Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
  2. Department of Botany and Plant Sciences, Institute of Integrative Genome Biology, University of California, Riverside, California 92521, USA
  3. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

Correspondence to: Jin-Biao Ma1,3 Correspondence and requests for materials should be addressed to J.-B.M. (Email: jma@biochemistry.uab.edu).

RNA silencing is a conserved regulatory mechanism in fungi, plants and animals that regulates gene expression and defence against viruses and transgenes1. Small silencing RNAs of approx20–30 nucleotides and their associated effector proteins, the Argonaute family proteins, are the central components in RNA silencing2. A subset of small RNAs, such as microRNAs and small interfering RNAs (siRNAs) in plants, Piwi-interacting RNAs in animals and siRNAs in Drosophila, requires an additional crucial step for their maturation; that is, 2'-O-methylation on the 3' terminal nucleotide3, 4, 5, 6. A conserved S-adenosyl-l-methionine-dependent RNA methyltransferase, HUA ENHANCER 1 (HEN1), and its homologues are responsible for this specific modification3, 4, 5, 7, 8. Here we report the 3.1 Å crystal structure of full-length HEN1 from Arabidopsis in complex with a 22-nucleotide small RNA duplex and cofactor product S-adenosyl-l-homocysteine. Highly cooperative recognition of the small RNA substrate by multiple RNA binding domains and the methyltransferase domain in HEN1 measures the length of the RNA duplex and determines the substrate specificity. Metal ion coordination by both 2' and 3' hydroxyls on the 3'-terminal nucleotide and four invariant residues in the active site of the methyltransferase domain suggests a novel Mg2+-dependent 2'-O-methylation mechanism.

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