Format

Send to

Choose Destination
See comment in PubMed Commons below
Nucleic Acids Res. 2016 Dec 15;44(22):10862-10878. Epub 2016 Oct 15.

RNA Editing TUTase 1: structural foundation of substrate recognition, complex interactions and drug targeting.

Author information

  • 1Department of Molecular Biology, University of Geneva, 1211 Geneva, Switzerland.
  • 2Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA.
  • 3Department of Chemistry & Biochemistry and the National Biomedical Computation Resource, University of California, San Diego, La Jolla, CA 92093, USA.
  • 4Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697, USA.
  • 5Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA ruslana@bu.edu.
  • 6Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA.
  • 7Department of Molecular Biology, University of Geneva, 1211 Geneva, Switzerland stephane.thore@inserm.fr.
  • 8INSERM, U1212, ARNA Laboratory, Bordeaux 33000, France.
  • 9CNRS UMR5320, ARNA Laboratory, Bordeaux 33000, France.
  • 10University of Bordeaux, ARNA Laboratory, Bordeaux 33000, France.

Abstract

Terminal uridyltransferases (TUTases) execute 3' RNA uridylation across protists, fungi, metazoan and plant species. Uridylation plays a particularly prominent role in RNA processing pathways of kinetoplastid protists typified by the causative agent of African sleeping sickness, Trypanosoma brucei In mitochondria of this pathogen, most mRNAs are internally modified by U-insertion/deletion editing while guide RNAs and rRNAs are U-tailed. The founding member of TUTase family, RNA editing TUTase 1 (RET1), functions as a subunit of the 3' processome in uridylation of gRNA precursors and mature guide RNAs. Along with KPAP1 poly(A) polymerase, RET1 also participates in mRNA translational activation. RET1 is divergent from human TUTases and is essential for parasite viability in the mammalian host and the insect vector. Given its robust in vitro activity, RET1 represents an attractive target for trypanocide development. Here, we report high-resolution crystal structures of the RET1 catalytic core alone and in complex with UTP analogs. These structures reveal a tight docking of the conserved nucleotidyl transferase bi-domain module with a RET1-specific C2H2 zinc finger and RNA recognition (RRM) domains. Furthermore, we define RET1 region required for incorporation into the 3' processome, determinants for RNA binding, subunit oligomerization and processive UTP incorporation, and predict druggable pockets.

PMID:
27744351
PMCID:
PMC5159558
DOI:
10.1093/nar/gkw917
[PubMed - in process]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems Icon for PubMed Central
    Loading ...
    Support Center