E2 interaction and dimerization in the crystal structure of TRAF6

Qian Yin, Su Chang Lin, Betty Lamothe, Miao Lu, Yu Chih Lo, Gregory Hura, Lixin Zheng, Rebecca L. Rich, Alejandro D. Campos, David G. Myszka, Michael J. Lenardo, Bryant G. Darnay, Hao Wu

Research output: Contribution to journalArticlepeer-review

226 Citations (Scopus)

Abstract

Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-6 mediates Lys63-linked polyubiquitination for NF-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.

Original languageEnglish
Pages (from-to)658-666
Number of pages9
JournalNature Structural and Molecular Biology
Volume16
Issue number6
DOIs
Publication statusPublished - 2009 Jun

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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