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Structure, interactions, and dynamics of the RING domain from human TRAF6.

Mercier P, Lewis MJ, Hau DD, Saltibus LF, Xiao W, Spyracopoulos L
Protein Sci 16 602-14 (2007)
Cited: 21 times
EuropePMC logo PMID: 17327397

Abstract

A key step in the signaling cascade responsible for activation of the transcription factor NF-kappaB involves Lys63-linked polyubiquitination of TRAF6. Covalent attachment of ubiquitin (Ub) to TRAF6, and subsequent poly(Ub) chain synthesis, is catalyzed by the hUev1a-hUbc13 heterodimer. hUbc13 is a catalytically competent E2 enzyme, and hUev1a is an E2-like protein that binds substrate Ub. The hUev1a-hUbc13 heterodimer is targeted to TRAF6 through interactions between hUbc13 and the N-terminal RING domain from TRAF6. Nuclear magnetic resonance (NMR) spectroscopy was used to determine the solution state structure of the RING domain from human TRAF6, and the interaction between hUbc13 and TRAF6 was characterized using NMR chemical shift mapping. The main-chain dynamics of the RING domain from TRAF6 were studied using (15)N NMR relaxation. Analysis of the main-chain dynamics data indicates that residues within the alpha-helix and beta-sheet of the RING domain are as rigid as regions of canonical secondary structure in larger proteins, consistent with the biological role of RING-domain E3 proteins, which requires that the E3 contain a recognition site for recruitment of E2 ubiquitin conjugation enzymes.

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  1. E2 interaction and dimerization in the crystal structure of TRAF6. Yin Q, Lin SC, Lamothe B, Lu M, Lo YC, Hura G, Zheng L, Rich RL, Campos AD, Myszka DG, Lenardo MJ, Darnay BG, Wu H. Nat Struct Mol Biol 16 658-666 (2009)
  2. Rice XB15, a protein phosphatase 2C, negatively regulates cell death and XA21-mediated innate immunity. Park CJ, Peng Y, Chen X, Dardick C, Ruan D, Bart R, Canlas PE, Ronald PC. PLoS Biol 6 e231 (2008)
  3. The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL. Lamothe B, Campos AD, Webster WK, Gopinathan A, Hur L, Darnay BG. J Biol Chem 283 24871-24880 (2008)
  4. Anti-Ro52 autoantibodies from patients with Sjögren's syndrome inhibit the Ro52 E3 ligase activity by blocking the E3/E2 interface. Espinosa A, Hennig J, Ambrosi A, Anandapadmanaban M, Abelius MS, Sheng Y, Nyberg F, Arrowsmith CH, Sunnerhagen M, Wahren-Herlenius M. J Biol Chem 286 36478-36491 (2011)
  5. Epigallocatechin-3-gallate(EGCG) suppresses melanoma cell growth and metastasis by targeting TRAF6 activity. Zhang J, Lei Z, Huang Z, Zhang X, Zhou Y, Luo Z, Zeng W, Su J, Peng C, Chen X. Oncotarget 7 79557-79571 (2016)
  6. The ubiquitin ligase TRAF6 negatively regulates the JAK-STAT signaling pathway by binding to STAT3 and mediating its ubiquitination. Wei J, Yuan Y, Jin C, Chen H, Leng L, He F, Wang J. PLoS One 7 e49567 (2012)
  7. Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1). Arcipowski KM, Stunz LL, Graham JP, Kraus ZJ, Vanden Bush TJ, Bishop GA. J Biol Chem 286 9948-9955 (2011)
  8. TR-FRET-based high-throughput screening assay for identification of UBC13 inhibitors. Madiraju C, Welsh K, Cuddy MP, Godoi PH, Pass I, Ngo T, Vasile S, Sergienko EA, Diaz P, Matsuzawa S, Reed JC. J Biomol Screen 17 163-176 (2012)
  9. A Residue Specific Insight into the Arkadia E3 Ubiquitin Ligase Activity and Conformational Plasticity. Birkou M, Chasapis CT, Marousis KD, Loutsidou AK, Bentrop D, Lelli M, Herrmann T, Carthy JM, Episkopou V, Spyroulias GA. J Mol Biol 429 2373-2386 (2017)
  10. Structural model of ubiquitin transfer onto an artificial RING finger as an E3 ligase. Miyamoto K. Sci Rep 4 6574 (2014)
  11. Cbl interacts with multiple E2s in vitro and in cells. Liyasova MS, Ma K, Voeller D, Ryan PE, Chen J, Klevit RE, Lipkowitz S. PLoS One 14 e0216967 (2019)
  12. Comprehensively surveying structure and function of RING domains from Drosophila melanogaster. Ying M, Huang X, Zhao H, Wu Y, Wan F, Huang C, Jie K. PLoS One 6 e23863 (2011)
  13. Homozygous deletion of RAG1, RAG2 and 5' region TRAF6 causes severe immune suppression and atypical osteopetrosis. Weisz Hubshman M, Basel-Vanagaite L, Krauss A, Konen O, Levy Y, Garty BZ, Smirin-Yosef P, Maya I, Lagovsky I, Taub E, Marom D, Gaash D, Shichrur K, Avigad S, Hayman-Manzur L, Villa A, Sobacchi C, Shohat M, Yaniv I, Stein J. Clin Genet 91 902-907 (2017)
  14. Benzoyl-xanthone derivative induces apoptosis in MCF-7 cells by binding TRAF6. Zhao X, Ren L, Wang X, Han G, Wang S, Yao Q, Qi Y. Exp Ther Med 23 181 (2022)


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