Elucidation of the substrate binding site of Siah ubiquitin ligase

Colin M House, Nancy C Hancock, Andreas Moller, Brett A Cromer, Victor Fedorov, David DL Bowtell, Michael William Parker, Galina Polekhina

Research output: Contribution to journalArticleResearchpeer-review

56 Citations (Scopus)

Abstract

The Siah family of RING proteins function as ubiquitin ligase components, contributing to the degradation of multiple targets involved in cell growth, differentiation, angiogenesis, oncogenesis, and inflammation. Previously, a binding motif (degron) was recognized in many of the Siah degradation targets, suggesting that Siah itself may facilitate substrate recognition. We report the crystal structure of the Siah in complex with a peptide containing the degron motif. Binding is within a groove formed in part by the zinc fingers and the first two beta strands of the TRAF-C domain of Siah. We show that residues in the degron, previously described to facilitate binding to Siah, interact with the protein. Mutagenesis of Siah at sites of interaction also abrogates both in vitro peptide binding and destabilization of a known Siah target.
Original languageEnglish
Pages (from-to)695 - 701
Number of pages7
JournalStructure
Volume14
Issue number4
Publication statusPublished - 2006

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