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


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.

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Figure 1: Interaction of C. elegans CUL-3 with BTB-domain-containing proteins.
Figure 2: Sequence requirements for interaction of BTB-domain-containing proteins with CUL-3.
Figure 3: MEL-26 associates with its genetic target, MEI-1.
Figure 4: MEL-26 interacts with the N terminus of MEI-1 through its MATH domain.


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We thank M. Peter for anti-CUL-3 and anti-MEL-26 antibodies. This work was supported by an NIH grant (to J.W.H. and S.J.E.), the Welch Foundation (to J.W.H.), and the National Human Genome Research Institute (to M.V.). Y.W. was supported by a Department of Defense predoctoral fellowship. S.J.E. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to J. Wade Harper.

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Xu, L., Wei, Y., Reboul, J. et al. BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3. Nature 425, 316–321 (2003).

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