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Letters to Nature

Nature 425, 311-316 (18 September 2003) | doi:10.1038/nature01959; Received 20 June 2003; Accepted 26 July 2003; Published online 3 September 2003

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The BTB protein MEL-26 is a substrate-specific adaptor of the CUL-3 ubiquitin-ligase

Lionel Pintard1,5, John H. Willis2,5, Andrew Willems3, Jacque-Lynne F. Johnson4, Martin Srayko4,6, Thimo Kurz2, Sarah Glaser1, Paul E. Mains4, Mike Tyers3, Bruce Bowerman2 & Matthias Peter1

  1. Institute of Biochemistry ETH, Hönggerberg 8093, Zürich, Switzerland
  2. Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA
  3. Department of Medical Genetics and Microbiology, Samuel Lunenfeld Research Institute, Mt Sinai Hosp., 600 University Ave., Univ. Toronto, Toronto, Ontario, M5G1X5, Canada
  4. Genes and Development Research Group and Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada
  5. These authors contributed equally to this work
  6. Present address: Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany

Correspondence to: Lionel Pintard1,5Matthias Peter1 Email: lionel.pintard@bc.biol.ethz.ch
Email: matthias.peter@bc.biol.ethz.ch

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Many biological processes, such as development and cell cycle progression are tightly controlled by selective ubiquitin-dependent degradation of key substrates. In this pathway, the E3-ligase recognizes the substrate and targets it for degradation by the 26S proteasome. The SCF (Skp1–Cul1–F-box) and ECS (Elongin C–Cul2–SOCS box) complexes are two well-defined cullin-based E3-ligases1, 2, 3. The cullin subunits serve a scaffolding function and interact through their C terminus with the RING-finger-containing protein Hrt1/Roc1/Rbx1, and through their N terminus with Skp1 or Elongin C, respectively. In Caenorhabditis elegans, the ubiquitin-ligase activity of the CUL-3 complex is required for degradation of the microtubule-severing protein MEI-1/katanin at the meiosis-to-mitosis transition4. However, the molecular composition of this cullin-based E3-ligase is not known. Here we identified the BTB-containing protein MEL-26 as a component required for degradation of MEI-1 in vivo. Importantly, MEL-26 specifically interacts with CUL-3 and MEI-1 in vivo and in vitro, and displays properties of a substrate-specific adaptor. Our results suggest that BTB-containing proteins may generally function as substrate-specific adaptors in Cul3-based E3-ubiquitin ligases.