In mammals, a similar ubiquitin ligase complex is formed, comprising Siah1, Ebi, and SIP (Siah interacting protein). In Drosophila, a ubiquitin ligase complex comprising Ebi, phyllopod, and sina interact to target tramtrack for ubiquitin-dependent proteolysis ( 8). Siah family proteins can interact with a multitude of cellular proteins as diverse as scaffold proteins such as phyllopod, transcriptional repressors such as tramtrack and nuclear receptor co-repressor (NCoR), the motor protein Kid, the oncogene β-catenin, and the tumor suppressor TGF-β induced early gene (TIEG-1) a more extensive list can be found in ref. The crystal structure of the substrate-binding domain is homologous to tumor necrosis factor (TNF) receptor associated factor (TRAF) proteins ( 5) and subsequent studies showed that Siah2, via degradation of TRAF2, was a regulator of TRAF2 signaling ( 6). Structurally, the Siah family have a divergent N-terminal 40 to 80 residues, but are highly conserved through the remaining RING domain and C-terminal, substrate-binding domain ( 3).
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