Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 16, Issue 6, Pages 658-U97Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.1605
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Funding
- US National Institutes of Health [RO1 AI045937, RO1 AR053540]
- US Department of Defense [DE-AC02-05CH11231]
- Intramural Research Program
- US National Institute of Allergy and Infectious Diseases
- Cancer Research Institute
- American Heart Association
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI045937, ZIAAI000717] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R01AR053540] Funding Source: NIH RePORTER
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Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-6 mediates Lys63-linked polyubiquitination for NF-kappa B activation via its N-terminal RING and zinc finger domains. Here we report the crystal structures of TRAF6 and its complex with the ubiquitin-conjugating enzyme (E2) Ubc13. The RING and zinc fingers of TRAF6 assume a rigid, elongated structure. Interaction of TRAF6 with Ubc13 involves direct contacts of the RING and the preceding residues, and the first zinc finger has a structural role. Unexpectedly, this region of TRAF6 is dimeric both in the crystal and in solution, different from the trimeric C-terminal TRAF domain. Structure-based mutagenesis reveals that TRAF6 dimerization is crucial for polyubiquitin synthesis and autoubiquitination. Fluorescence resonance energy transfer analysis shows that TRAF6 dimerization induces higher-order oligomerization of full-length TRAF6. The mismatch of dimeric and trimeric symmetry may provide a mode of infinite oligomerization that facilitates ligand-dependent signal transduction of many immune receptors.
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