5WZZ

The SIAH E3 ubiquitin ligases promote Wnt/ beta-catenin signaling through mediating Wnt-induced Axin degradation

Summary for 5WZZ

• Entry DOI: 10.2210/pdb5wzz/pdb
• Descriptor: E3 ubiquitin-protein ligase SIAH1, Axin-1, ZINC ION, ... (4 entities in total)
• Functional Keywords: protein complex, wnt pathway, ligase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm: Q8IUQ4 O15169
• Total number of polymer chains: 8
• Total formula weight: 96052.73

Authors

Ji, L.,Jiang, B.,Jiang, X.,Charlat, O.,Chen, A.,Mickanin, C.,Bauer, A.,Xu, W.,Yan, X.-X.,Cong, F. (deposition date: 2017-01-19, release date: 2017-08-16, Last modification date: 2023-11-22)

Primary citation

Ji, L.,Jiang, B.,Jiang, X.,Charlat, O.,Chen, A.,Mickanin, C.,Bauer, A.,Xu, W.,Yan, X.-X.,Cong, F.
The SIAH E3 ubiquitin ligases promote Wnt/ beta-catenin signaling through mediating Wnt-induced Axin degradation
Genes Dev., 31:904-915, 2017

PubMed Abstract: The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling.

PubMed: 28546513
DOI: 10.1101/gad.300053.117

Experimental method

X-RAY DIFFRACTION (2.103 Å)