1. Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling.
- Author
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Polekhina G, House CM, Traficante N, Mackay JP, Relaix F, Sassoon DA, Parker MW, and Bowtell DD
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, Crystallography, X-Ray, Dimerization, Humans, Mice, Models, Molecular, Molecular Sequence Data, NF-kappa B metabolism, Peptide Fragments chemistry, Peptide Fragments metabolism, Protein Binding, Protein Structure, Quaternary, Protein Structure, Tertiary, Receptors, Tumor Necrosis Factor metabolism, Sequence Alignment, Sequence Homology, Amino Acid, Transcriptional Activation drug effects, Ubiquitin-Protein Ligases, Zinc metabolism, Zinc Fingers, Nuclear Proteins chemistry, Nuclear Proteins metabolism, Proteins, Receptors, Tumor Necrosis Factor chemistry, Signal Transduction drug effects, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Members of the Siah (seven in absentia homolog) family of RING domain proteins are components of E3 ubiquitin ligase complexes that catalyze ubiquitination of proteins. We have determined the crystal structure of the substrate-binding domain (SBD) of murine Siah1a to 2.6 A resolution. The structure reveals that Siah is a dimeric protein and that the SBD adopts an eight-stranded beta-sandwich fold that is highly similar to the TRAF-C region of TRAF (TNF-receptor associated factor) proteins. The TRAF-C region interacts with TNF-alpha receptors and TNF-receptor associated death-domain (TRADD) proteins; however, our findings indicate that these interactions are unlikely to be mimicked by Siah. The Siah structure also reveals two novel zinc fingers in a region with sequence similarity to TRAF. We find that the Siah1a SBD potentiates TNF-alpha-mediated NF-kappa B activation. Therefore, Siah proteins share important similarities with the TRAF family of proteins, including their overall domain architecture, three-dimensional structure and functional activity.
- Published
- 2002
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