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Letters to Nature

Nature 425, 316-321 (18 September 2003) | doi:10.1038/nature01985; Received 15 July 2003; Accepted 14 August 2003; Published online 3 September 2003

BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3

Lai Xu1,6, Yue Wei2,6, Jerome Reboul5,7, Philippe Vaglio5, Tae-Ho Shin4, Marc Vidal5, Stephen J. Elledge1,3,7 & J. Wade Harper1,2,7

  1. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
  2. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
  3. Howard Hughes Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
  4. Department of Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA
  5. Dana Farber Cancer Institute, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
  6. These authors contributed equally to this work
  7. Present addresses: Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA (J.W.H.); Center for Genetics and Genomics, Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA (S.J.E.); and INSERM Unite 119, Institut Paoli Calmette, 13009 Marseille, France (J.R.)

Correspondence to: J. Wade Harper1,2,7 Email: wade_harper@hms.harvard.edu

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Programmed destruction of regulatory proteins through the ubiquitin–proteasome system is a widely used mechanism for controlling signalling pathways1, 2. Cullins3 are proteins that function as scaffolds for modular ubiquitin ligases typified by the SCF (Skp1–Cul1–F-box) complex4, 5, 6. The substrate selectivity of these E3 ligases is dictated by a specificity module that binds cullins. In the SCF complex, this module is composed of Skp1, which binds directly to Cul1, and a member of the F-box family of proteins4, 5, 6, 7. F-box proteins bind Skp1 through the F-box motif7, and substrates by means of carboxy-terminal protein interaction domains1, 2, 5. Similarly, Cul2 and Cul5 interact with BC-box-containing specificity factors through the Skp1-like protein elongin C2. Cul3 is required for embryonic development in mammals and Caenorhabditis elegans8, 9, 10 but its specificity module is unknown. Here we report the identification of a large family of BTB-domain proteins as substrate-specific adaptors for C. elegans CUL-3. Biochemical studies using the BTB protein MEL-26 and its genetic target MEI-1 (refs 12, 13) indicate that BTB proteins merge the functional properties of Skp1 and F-box proteins into a single polypeptide.