title: Siah ubiquitin ligase is structurally related to TRAF and modulates TNF-alpha signaling.
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.
authors.affiliation: Biota Structural Biology Laboratory, St. Vincent's Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
authors.forename: Galina
authors.initials: G
authors.lastname: Polekhina
authors.forename: Colin M
authors.initials: CM
authors.lastname: House
authors.forename: Nadia
authors.initials: N
authors.lastname: Traficante
authors.forename: Joel P
authors.initials: JP
authors.lastname: Mackay
authors.forename: Frédéric
authors.initials: F
authors.lastname: Relaix
authors.forename: David A
authors.initials: DA
authors.lastname: Sassoon
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers; D000098563:Seven in Absentia Proteins
chemical_list: D016328:NF-kappa B; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C484442:Siah1a protein, mouse; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; D015032:Zinc